N-linked urea or carbamate of heterocyclic thioesters for vision and memory disorders

ABSTRACT

The present invention relates to pharmaceutical compositions comprising and methods of using an N-linked urea or carbamate of a heterocyclic thioester for treating a vision disorder, improving vision, treating memory impairment, or enhancing memory performance.

BACKGROUND OF THE INVENTION

1. Field of Invention

This invention relates to pharmaceutical compositions and methods fortreating vision loss, preventing vision degeneration, and promotingvision regeneration (“neopsis”) using low molecular weight, smallmolecule derivatives.

2. Description of Related Art

The visual system is composed of the eyes, ocular adnexa and the visualpathways. Dysfunction of the visual system may lead to permanent ortemporary visual impairment, i.e. a deviation from normal in one or morefunctions of the eye. Visual impairment manifests itself in various waysand includes a broad range of visual dysfunctions and disturbances.Without limitation, these dysfunctions and disturbances include partialor total loss of vision, the need for correction of visual acuity forobjects near and far, loss of visual field, impaired ocular motilitywithout diplopia (double vision), impaired or skewed color perception,limited adaptation to light and dark, diminished accommodation,metamorphopsic distortion, impaired binocular vision, paresis ofaccommodation, iridoplegia, entropion, ectropion, epiphora,lagophthalmos, and scarring. See Physicians' Desk Reference (PDR) forOphthalmology, 16th Edition, 6:47 (1988). The visual system may beadversely affected by various ophthalmologic disorders, diseases,injuries, and complications, including, without limitation, geneticdisorders; [non-genetic disorders;] disorders associated with aging ordegenerative diseases; disorders correlating to physical injury to theeye, head, or other parts of the body resulting from external forces;disorders resulting from environmental factors; disorders resulting froma broad range of diseases; and combinations of any of the above.

The visual system is a complex system composed of numerous components.Visual impairment can involve the entire visual system, any onecomponent, or any combination of components, depending upon the precisenature of the circumstances. The eye is composed of a lens, which issuspended in the zonules of Zinn and is focused by the ciliary body. Theciliary body also secretes aqueous humor, which fills the posteriorchamber, passes through the pupil into the anterior chamber, then drainsprimarily via the canal of Schlemm. The iris regulates the quantity oflight entering the eye by adjusting the size of its central opening, thepupil. A visual image is focused onto the retina, the fovea centralisbeing the retinal area of sharpest visual acuity. The conjunctiva is themucus membrane which lines the eyelids and the eyeball, and endsabruptly at the limbus conjunctivae, the edge of the conjunctivaoverlapping the cornea. The cornea is the clear, transparent anteriorportion of the fibrous coat of the eye; it is important in lightrefraction and is covered with an epithelium that differs in manyrespects from the conjunctival epithelium.

The retina is the innermost, light sensitive portion of the eye,containing two types of photoreceptors, cones, which are responsible forcolor vision in brighter light, and rods, which are essential for visionin dim light but do not perceive colors. After light passes through thecornea, lens system, and the vitreous humor, it enters the retina fromthe inside; that is, it passes through the ganglion cells and nervefibers, the inner and outer plexiform layers, the inner and outernuclear layers, and the internal and external limiting membranes beforeit finally reaches the layer of photoreceptors located near the outsideof the retina, just inside the outermost pigment epithelium layer. Thecells of the pigment epithelium layer act as an anatomical barrier toliquids and substances located outside of the eye, forming the“blood-retina” barrier, and provide nourishment, oxygen, a source offunctionally useful substances like vitamin A, and phagocytosis ofdecomposition products to photoreceptor cells. There is no anatomicalconnection between the pigment epithelium and the photoreceptor layer,permitting separation of the layers in some pathological situations.

When rods or cones are excited by light, signals are transmitted throughsuccessive neurons in the retina itself, into the optic nerve fibers,and ultimately to the cerebral cortex. Both rods and cones containmolecules that decompose on exposure to light and, in the process,excite the nerve fibers leading from the eye. The molecule in rods isrhodopsin. The three light-sensitive molecules in cones, collectivelycalled iodopsin, have compositions only slightly different from that ofrhodopsin and are maximally excited by red, blue, or green light,respectively.

Neither rods nor cones generate action potentials. Rather, thelight-induced membrane hyperpolarization generated in the outer,photosensitive segment of a rod or cone cell is transmitted from theouter segment through the inner segment to the synaptic body by directconduction of the electrical voltage itself, a process calledelectrotonic conduction. At the synaptic body, the membrane potentialcontrols the release of an unknown transmitter molecule. In low Light,rod and cone cell membranes are depolarized and the rate of transmitterrelease is greatest. Light-induced hyperpolarization causes a markeddecrease in the release of transmitter molecules.

The transmitters released by rod and cone cells induce signals in thebipolar neurons and horizontal cells. The signals in both these cellsare also transmitted by electrotonic conduction and not by actionpotential.

The rod bipolar neurons connect with as many as 50 rod cells, while thedwarf and diffuse bipolar cells connect with one or several cone cells.A depolarizing bipolar cell is stimulated when its connecting rods orcones are exposed to light. The release of transmitter moleculesinhibits the depolarizing bipolar cell. Therefore, in the dark, when therods and cones are secreting large quantities of transmitter molecules,the depolarizing bipolar cells are inhibited. In the light, the decreasein release of transmitter molecules from the rods and cones reduces theinhibition of the bipolar cell, allowing it to become excited. In thismanner, both positive and negative signals can be transmitted throughdifferent bipolar cells from the rods and cones to the amacrine andganglion cells.

As their name suggests, horizontal cells project horizontally in theretina, where they may synapse with rods, cones, other horizontal cells,or a combination of cells types. The function of horizontal cells isunclear, although some mechanism in the convergence of photoreceptorsignaling has been postulated.

All types of bipolar cells connect with ganglion cells, which are of twoprimary types. A-type ganglion cells predominately connect with rodbipolar cells, while B-type ganglion cells predominately connect withdwarf and diffuse bipolar cells. It appears that A-type ganglion cellsare sensitive to contrast, light intensity, and perception of movement,while B-type ganglion cells appear more concerned with color vision andvisual acuity.

Like horizontal cells, the Amacrine cells horizontally synapse withseveral to many other cells, in this case bipolar cells, ganglion cells,and other Amacrine cells. The function of Amacrine cells is alsounclear.

The axons of ganglion cells carry signals into the nerve fiber layer ofthe eye, where the axons converge into fibers which further converge atthe optic disc, where they exit the eye as the optic nerve. The ganglioncells transmit their signals through the optic nerve fibers to the brainin the form of action potentials. These cells, even when unstimulated,transmit continuous nerve impulses at an average, baseline rate of about5 per second. The visual signal is superimposed onto this baseline levelof ganglion cell stimulation. It can be either an excitatory signal,with the number of impulses increasing above the baseline rate, or aninhibitory signal, with the number of nerve impulses decreasing belowthe baseline rate.

As part of the central nervous system, the eye is in some ways anextension of the brain; as such, it has a limited capacity forregeneration. This limited regeneration capacity further complicates thechallenging task of improving vision, resolving dysfunction of thevisual system, and/or treating or preventing ophthalmologic disorders.Many disorders of the eye, such as retinal photic injury, retinalischemia-induced eye injury, age-related macular degeneration, freeradical-induced eye diseases, as well as numerous other disorders, areconsidered to be entirely untreatable. Other ophthalmologic disorders,e.g., disorders causing permanent visual impairment, are corrected onlyby the use of ophthalmic devices and/or surgery, with varying degrees ofsuccess.

The immunosuppressant drugs FK506, rapamycin, and cyclosporin are wellknown as potent T-cell specific immunosuppressants, and are effectiveagainst autoimmunity, transplant or graft rejection, inflammation,allergic responses, other autoimmune or immune-mediated diseases, andinfectious diseases. It has been disclosed that application ofCyclosporin, FK-506, Rapamycin, Buspirone, Spiperone, and/or theirderivatives are effective in treating some ophthalmologic disorders ofthese types. Several ophthalmologic disorders or vision problems areknown to be associated with autoimmune and immunologically-mediatedactivities; hence, immunomodulatory compounds are expected todemonstrate efficacy for treating those types of ophthalmologicdisorders or vision problems.

The effects of FK506, Rapamycin, and related agents in the treatment ofophthalmologic diseases are disclosed in several U.S. patents (Goulet etal., U.S. Pat. No. 5,532,248; Mochizuki et al., U.S. Pat. No. 5,514,686;Luly et al., U.S. Pat. No. 5,457,111; Russo et al., U.S. Pat. No.5,441,937; Kulkarni, U.S. Pat. No. 5,387,589; Asakura et al., U.S. Pat.No. 5,368,865; Goulet et al., U.S. Pat. No. 5,258,389; Armistead et al.,U.S. Pat. No. 5,192,773; Goulet et al., U.S. Pat. No. 5,189,042; andFehr, U.S. Pat. No. 5,011,844). These patents claim FK506 or Rapamycinrelated compounds and disclose the known use of FK506 or Rapamycinrelated compounds in the treatment of ophthalmologic disorders inassociation with the known immunosuppressive effects of FK506 andRapamycin. The compounds disclosed in these patents are relativelylarge. Further, the cited patents relate to immunomodulatory compoundslimited to treating autoimmunity or related diseases, orimmunologically-mediated diseases, for which the efficacy of FK506 andRapamycin is well known.

Other U.S. patents disclose the use of cyclosporin, Spiperone,Buspirone, their derivatives, and other immunosuppressive compounds foruse in the treatment of ophthalmologic diseases (Sharpe et al., U.S.Pat. No. 5,703,088; Sharpe et al., U.S. Pat. No. 5,693,645; Sullivan,U.S. Pat. No. 5,688,765; Sullivan, U.S. Pat. No. 5,620,921; Sharpe etal., U.S. Pat. No. 5,574,041; Eberle, U.S. Pat. No. 5,284,826; Sharpe etal., U.S. Pat. No. 5,244,902; Chiou et al., U.S. Pat. Nos. 5,198,454 and5,194,434; and Kaswan, U.S. Pat. No. 4,839,342). These patents alsorelate to compounds useful for treating autoimmune diseases and cite theknown use of cyclosporin, Spiperone, Buspirone, their derivatives, andother immunosuppressive compounds in treating ocular inflammation andother immunologically-mediated ophthalmologic diseases.

The immunosuppressive compounds disclosed in the prior art suppress theimmune system, by definition, and also exhibit other toxic side effects.Accordingly, there is a need for non-immunosuppressant, small moleculecompounds, and compositions and methods for use of such compounds, thatare useful in improving vision; preventing, treating, and/or repairingvisual impairment or dysfunction of the visual system; and preventing,treating, and/or resolving ophthalmologic disorders.

There are also a number of patents on non-immunosuppressive compoundsdisclosing methods of use for permitting or promoting wound healing(whether from injury or surgery); controlling intraocular pressure(often resulting from glaucoma); controlling neurodegenerative eyedisorders, including damage or injury to retinal neurons, damage orinjury to retinal ganglion cells, and macular degeneration; stimulatingneurite outgrowth; preventing or reducing oxidative damage caused byfree radicals; and treating impaired oxygen and nutrient supply, as wellas impaired waste product removal, resulting from low blood flow. Thesenon-immunosuppressive substances fall into one of two generalcategories: naturally occurring molecules, such as proteins,glycoproteins, peptides, hormones, and growth factors; and syntheticmolecules.

Within the group of naturally occurring non-immunosuppressive molecules,several hormones, growth factors, and signaling molecules have beenpatented for use as supplements to naturally occurring quantities ofsuch molecules, as well as for targeting of specific cells where theparticular molecule does not naturally occur in a mature individual.These patents generally claim methods of use for reducing or preventingthe symptoms of ocular disease, or arresting or reversing vision loss.

Specifically, Louis et al., U.S. Pat. Nos. 5,736,516 and 5,641,749,disclose the use of a glial cell line derived neurotrophic factor (GDNF)to stop or reverse the degeneration of retinal neurons (i.e.photoreceptors) and retinal ganglion cells caused by glaucoma, or otherdegenerative or traumatic retinal diseases or injuries. O'Brien, et al.,U.S. Pat. Nos. 5,714,459 and 5,700,909, disclose the use of aglycoprotein, Saposin, and its derivatives for stimulating neuriteoutgrowth and increasing myelination. To stop or reverse degeneration ofretinal neurons, LaVail et al., U.S. Pat. No. 5,667,968, discloses theuse of a variety of neurotrophic proteins, including brain-derivedneurotrophic factor, ciliary neurotrophic factor, neurotrophin-3 orneurotrophin-4, acidic or basic fibroblast growth factors, interleukin,tumor necrosis factor-α, insulin-like growth factor-2 and other growthfactors. Wong et al., U.S. Pat. No. 5,632,984, discloses the use ofinterferons, especially interferon α-2a, for treating the symptoms ofmacular degeneration by reducing hemorrhage and limitingneovascularization. finally, Wallace et al., U.S. Pat. No. 5,441,937,discloses the use of a lung-derived neurotrophic factor (NTF) tomaintain the functionality of ciliary ganglion and parasympatheticneuron cells.

A key characteristic of factors derived from specific cell lines istheir localization to specific cell lines or tissues; systemic treatmentwith these molecules would run a substantial risk of unintended, andpotentially dangerous, effects in cell lines where the genes encodingthese molecules are inactive. Similarly, hormones and growth factorsoften activate a large number of genes in many cell lines; again,non-localized application of these molecules would run a substantialrisk of provoking an inappropriate, and potentially dangerous, response.

Within the category of synthetic molecules, most of the patentedcompounds are immunosuppressive and disclose uses in treatinginflammatory, autoimmune, and allergic responses, as discussed above. Afew others are non-immunosuppressive and claim the ability to treatcellular degeneration, and in some cases promote cellular regeneration,most often in the context of their antioxidant properties.

Specifically, Tso et al., U.S. Pat. No. 5,527,533, discloses the use ofastaxanthin, a carotenoid antioxidant, for preventing or reducingphotoreceptor damage resulting from the presence of free radicals.Similarly, Babcock et al., U.S. Pat. No. 5,252,319, discloses the use ofantioxidant aminosteroids for treating eye disease and injury, byincreasing resistance to oxidative damage. Freeman, U.S. Pat. No.5,468,752, discloses the use of the antiviralphosphonylmethoxyalkylcytosines to reduce abnormally increasedintraocular pressure.

Hamilton and Steiner disclose in U.S. Pat. No. 5,614,547 novelpyrrolidine carboxylate compounds which bind to the immunophilin FKBP12and stimulate nerve growth, but which lack immunosuppressive effects.Unexpectedly, it has been discovered that these non-immunosuppressantcompounds promote improvements in vision and resolve ophthalmologicdisorders. Yet their novel small molecule structure andnon-immunosuppressive properties differentiate them from FK506 andrelated immunosuppressive compounds found in the prior art.

Further, these compounds may be differentiated from thenon-immunosuppressive compounds used to treat vision disorders by theirnovel small molecule structure and their lack of general, systemiceffects. Naturally occurring hormones, growth factors, cytokines, andsignaling molecules are generally multifunctional and activate manygenes in diverse cell lines. The present compounds do not, thus avoidingthe unexpected, and potentially dangerous, side effects of systemic use.Similarly, the present compounds also avoid the potential unexpectedside effects of introducing cell line-specific molecules into other celllines were they do not naturally occur.

SUMMARY OF THE INVENTION

The present invention relates to a method for treating a visiondisorder, improving vision, treating memory impairment, or enhancingmemory performance in an animal, which comprises administering to saidanimal an effective amount of an N-linked urea or carbamate of aheterocyclic thioester compound.

The present invention further relates to a pharmaceutical compositionfor treating a vision disorder or improving vision or treating memoryimpairment or enhancing memory performance in an animal which comprises

(i) an effective amount of an N-linked urea or carbamate of aheterocyclic thioester compound for treating a vision disorder orimproving vision or treating memory impairment or enhancing memoryperformance in an animal; and

(ii) a pharmaceutically acceptable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A, B and C show that GPI 1046 protects retinal ganglion cellsagainst degeneration following retinal ischemia.

FIG. 2 shows that GPI 1046 prevents degeneration of optic nerve axonsand myelin following retinal ischemia.

FIG. 3 shows that GPI 1046 provides moderate protection against retinalganglion cell death after optic nerve transection.

FIG. 4 shows that GPI 1046 treatment duration significantly affects theprocess of optic nerve axonal degeneration after transection.

FIG. 5 shows that GPI 1046 treatment produces a greater effect on opticnerve axons than ganglion cell bodies.

FIG. 6 shows that GPI 1046 treatment for 28 days after optic nervetransection prevents myelin degeneration in the proximal stump.

FIG. 7 shows that FKBP-12 immunohistochemistry labels oligodendroglia(large dark cells with fibrous processes), the cells which producemyelin, located between the fascicles of optic nerve fibers, and alsosome optic nerve axons.

FIG. 8 shows GPI 1046 treatment for 28 days after optic nervetransection prevents myelin degeneration in the distal stump.

FIG. 9 shows that 28 day treatment with GPI 1046 treatment beginning 8weeks after onset of streptozotocin induced diabetes decreases theextent of neovascularization in the inner and outer retina and protectsneurons in the inner nuclear layer (INL) and ganglion cell layer (GCL)from degeneration.

DETAILED DESCRIPTION OF THE INVENTION Definitions

“Eye” refers to the anatomical structure responsible for vision inhumans and other animals, and encompasses the following anatomicalstructures, without limitation: lens, vitreous body, ciliary body,posterior chamber, anterior chamber, pupil, cornea, iris, canal ofSchlemm, zonules of Zinn, limbus, conjunctiva, choroid, retina, centralvessels of the retina, optic nerve, fovea centralis, macula lutea, andsclera.

“GPI 1605” refers to a compound of formula

“GPI 1046” refers to 3-(3-pyridyl)-1-propyl(2s)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, acompound of formula

“GPI 1312” refers to a compound of formula

“GPI 1572” refers to a compound of formula

“GPI 1389” refers to a compound of formula

“GPI 1511” refers to a compound of formula

“GPI 1234” refers to a compound of formula

“Isomers” refer to different compounds that have the same molecularformula. “Stereoisomers” are isomers that differ only in the way theatoms are arranged in space. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other.“Diastereoisomers” are stereoisomers which are not mirror images of eachother. “Racemic mixture” means a mixture containing equal parts ofindividual enantiomers. “Non-racemic mixture” is a mixture containingunequal parts of individual enantiomers or sterecisomers.

“Enhancing memory performance” refers to improving or increasing themental faculty by which to register, retain or recall past experiences,knowledge, ideas, sensations, thoughts or impressions.

“Memory impairment” refers to a diminished mental registration,retention or recall of past experiences, knowledge, ideas, sensations,thoughts or impressions. Memory impairment may affect short andlong-term information retention, facility with spatial relationships,memory (rehearsal) strategies, and verbal retrieval and production.Common causes of memory impairment are age, severe head trauma, brainanoxia or ischemia, alcoholic-nutritional diseases, and drugintoxications. Examples of memory impairment include, withoutlimitation, benign forgetfulness, amnesia and any disorder in whichmemory deficiency is present, such as Korsakoff's amnesic psychosis,dementia and learning disorders.

“Neopsic factors” or “neopsics” refers to compounds useful in treatingvision loss, preventing vision degeneration, or promoting visionregeneration.

“Neopsis” refers to the process of treating vision loss, preventingvision degeneration, or promoting vision regeneration.

“Ophthalmological” refers to anything about or concerning the eye,without limitation, and is used interchangeably with “ocular,”“ophthalmic,” “ophthalmologic,” and other such terms, withoutlimitation.

“Pharmaceutically acceptable salt, ester, or solvate” refers to a salt,ester, or solvate of a subject compound which possesses the desiredpharmacological activity and which is neither biologically nor otherwiseundesirable. A salt, ester, or solvate can be formed with inorganicacids such as acetate, adipate, alginate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, naphthylate, 2-naphthalenesulfonate, nicotinate,oxalate, sulfate, thiocyanate, tosylate and undecanoate. Examples ofbase salts, esters, or solvates include ammonium salts; alkali metalsalts, such as sodium and potassium salts; alkaline earth metal salts,such as calcium and magnesium salts; salts with organic bases, such asdicyclohexylamine salts; N-methyl-D-glucamine; and salts with aminoacids, such as arginine, lysine, and so forth. Also, the basicnitrogen-containing groups can be quarternized with such agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl chlorides,bromides, and iodides; dialkyl sulfates, such as dimethyl, diethyl,dibutyl, and diamyl sulfates; long chain halides, such as decyl, lauryl,myristyl, and stearyl chlorides, bromides, and iodides; aralkyl halides,such as benzyl and phenethyl bromides; and others. Water or oil-solubleor dispersible products are thereby obtained.

“Preventing vision degeneration” refers to the ability to preventdegeneration of vision in patients newly diagnosed as having adegenerative disease affecting vision, or at risk of developing a newdegenerative disease affecting vision, and for preventing furtherdegeneration of vision in patients who are already suffering from orhave symptoms of a degenerative disease affecting vision.

“Promoting vision regeneration” refers to maintaining, improving,stimulating or accelerating recovery of, or revitalizing one or morecomponents of the visual system in a manner which improves or enhancesvision, either in the presence or absence of any ophthalmologicdisorder, disease, or injury.

“Treating” refers to:

(i) preventing a disease and/or condition from occurring in a subjectwhich may be predisposed to the disease and/or condition but has not yetbeen diagnosed as having it;

(ii) inhibiting the disease and/or condition, i.e., arresting itsdevelopment; or

(iii) relieving the disease and/or condition, i.e., causing regressionof the disease and/or condition.

“Vision” refers to the ability of humans and other animals to processimages, and is used interchangeably with “sight”, “seeing”, and othersuch terms, without limitation.

“Vision disorder” refers to any disorder that affects or involvesvision, including without limitation visual impairment, orbitaldisorders, disorders of the lacrimal apparatus, disorders of theeyelids, disorders of the conjunctiva, disorders of the cornea,cataracts, disorders of the uveal tract, disorders of the retina,disorders of the optic nerve or visual pathways, free radical inducedeye disorders and diseases, immunologically-mediated eye disorders anddiseases, eye injuries, and symptoms and complications of eye disease,eye disorder, or eye injury.

“Visual impairment” refers to any dysfunction in vision includingwithout limitation disturbances or diminution in vision (e.g.,binocular, central, peripheral, scotopic), visual acuity for objectsnear and far, visual field, ocular motility, color perception,adaptation to light and dark, accommodation, refraction, andlacrimation. See Physician's Desk Reference (PDR) for Ophthalmology,16^(th) Edition, 6:47 (1988).

Methods of the Present Invention

The present invention relates to a method of treating a vision disorder,improving vision, treating memory impairment, or enhancing memoryperformance in an animal, which comprises administering to said animalan effective amount of a derivative.

The inventive methods are particularly useful for treating various eyedisorders including but not limited to visual disorders, diseases,injuries, and complications, genetic disorders; disorders associatedwith aging or degenerative vision diseases; vision disorders correlatingto physical injury to the eye, head, or other parts of the bodyresulting from external forces; vision disorders resulting fromenvironmental factors; vision disorders resulting from a broad range ofdiseases; and combinations of any of the above.

In particular, the compositions and methods of the present invention areuseful for improving vision, or correcting, treating, or preventingvisual (ocular) impairment or dysfunction of the visual system,including permanent and temporary visual impairment, without limitation.The present invention is also useful in preventing and treatingophthalmologic diseases and disorders, treating damaged and injuredeyes, and preventing and treating diseases, disorders, and injurieswhich result in vision deficiency, vision loss, or reduced capacity tosee or process images, and the symptoms and complications resulting fromsame. The eye diseases and disorders which may be treated or preventedby the compositions and methods of the present invention are not limitedwith regard to the cause of said diseases or disorders. Accordingly,said compositions and methods are applicable whether the disease ordisorder is caused by genetic or environmental factors, as well as anyother influences. The compositions and methods of the present inventionare particularly useful for eye problems or vision loss or deficiencyassociated with all of the following, without limitation: aging,cellular or physiological degeneration, central nervous system orneurological disorder, vascular defects, muscular defects, and exposureto adverse environmental conditions or substances.

The compositions and methods of the present invention are particularlyuseful in correcting, treating, or improving visual impairment, withoutlimitation. Visual impairment in varying degrees occurs in the presenceof a deviation from normal in one or more functions of the eye,including (1) visual acuity for objects at distance and near; (2) visualfields; and (3) ocular motility without diplopia. See Physicians' DeskReference (PDR) for Ophthalmology, 16th Edition, 6:47 (1988). Vision isimperfect without the coordinated function of all three. Id.

Said compositions and methods of use are also useful in correcting,treating, or improving other ocular functions including, withoutlimitation, color perception, adaptation to light and dark,accommodation, metamorphopsia, and binocular vision. The compositionsand methods of use are particularly useful in treating, correcting, orpreventing ocular disturbances including, without limitation, paresis ofaccommodation, iridoplegia, entropion, ectropion, epiphora,lagophthalmos, scarring, vitreous opacities, non-reactive pupil, lightscattering disturbances of the cornea or other media, and permanentdeformities of the orbit.

The compositions and methods of use of the present invention are alsohighly useful in improving vision and treating vision loss. Vision lossranging from slight loss to absolute loss may be treated or preventedusing said compositions and methods of use. Vision may be improved bythe treatment of eye disorders, diseases, and injuries using thecompositions and methods of the invention. However, improvements invision using the compositions and methods of use are not so limited, andmay occur in the absence of any such disorder, disease, or injury.

The compositions and methods of the present invention are also useful inthe treatment or prevention of the following non-limiting exemplarydiseases and disorders, and symptoms and complications resultingtherefrom.

Vision disorders include but are not limited to the following:

visual impairment, such as diminished visual acuity for objects near andfar, visual fields, and ocular motility;

orbital disorders, such as orbital cellulitis, periorbital cellulitis,cavernous sinus thrombosis, and exophthalmos (proptosis);

disorders of the lacrimal apparatus, such as dacryostenosis, congenitaldacryostenosis, and dacryocystitis (acute or chronic);

disorders of the eyelids, such as lid edema, blepharitis, ptosis, Bell'spalsy, blepharospasm, hordeolum (stye), external hordeolum, internalhordeolum (meibomian stye), chalazion, entropion (inversion of theeyelid), ectropion (eversion of the eyelid), tumors (benign andmalignant), xanthelasma, basil cell carcinoma, squamous cell carcinoma,meibomian gland carcinoma, and melanoma;

disorders of the conjunctiva, such as pinguecula, pterygium, and otherneoplasms, acute conjunctivitis, chronic conjunctivitis, adultgonococcal conjunctivitis, neonatal conjunctivitis, trachoma (granularconjunctivitis or Egyptian ophthalmia), inclusion conjunctivitis(inclusion blenorrhea or swimming pool conjunctivitis), neonatalinclusion conjunctivitis, adult inclusion conjunctivitis, vernalkeratoconjunctivitis, keratoconjunctivitis sicca (keratitis sicca or dryeye syndrome), episcleritis, scleritis, cicatricial pemphigoid (ocularcicatricial pemphigoid or benign mucous membrane pemphigoid), andsubconjunctival hemorrhage;

disorders of the cornea, such as superficial punctate keratitis, cornealulcer, indolent ulcer, recurrent corneal erosion, corneal epithelialbasement membrane dystrophy, corneal endothelial cell dystrophy, herpessimplex keratitis (herpes simplex keratoconjunctivitis), dendritickeratitis, disciform keratitis, ophthalmic herpes zoster, phlyctenularkeratoconjunctivitis (phlyctenular or eczematous conjunctivitis),interstitial keratitis (parenchymatous keratitis), peripheral ulcerativekeratitis (marginal keratolysis or peripheral rheumatoid ulceration),keratomalacia (xerotic keratitis), xerophthalmia, keratoconus, bullouskeratopathy;

cataracts, including developmental or congenital cataracts, juvenile oradult cataracts, nuclear cataract, posterior subcapsular cataracts;

disorders of the uveal tract, such as uveitis (inflammation of the uvealtract or retina), anterior uveitis, intermediate uveitis, posterioruveitis, iritis, cyclitis, choroiditis, ankylosing spondylitis, Reiter'ssyndrome, pars planitis, toxoplasmosis, cytomegalovirus (CMV), acuteretinal necrosis, toxocariasis, birdshot choroidopathy, histoplasmosis(presumed ocular histoplasmosis syndrome), Behcet's syndrome,sympathetic ophthalmia, Vogt-Koyanagi-Harada syndrome, sarcoidosis,reticulum cell sarcoma, large cell lymphoma, syphilis, tuberculosis,juvenile rheumatoid arthritis, endophthalmitis, and malignant melanomaof the choroid;

disorders of the retina, such as vascular retinopathies (e.g.,arteriosclerotic retinopathy and hypertensive retinopathy), central andbranch retinal artery occlusion, central and branch retinal veinocclusion, diabetic retinopathy (e.g., proliferative retinopathy andnon-proliferative retinopathy), macular degeneration of the aged(age-related macular degeneration or senile macular degeneration),neovascular macular degeneration, retinal detachment, retinitispigmentosa, retinal photic injury, retinal ischemia-induced eye injury,and glaucoma (e.g., primary glaucoma, chronic open-angle glaucoma, acuteor chronic angle-closure, congenital (infantile) glaucoma, secondaryglaucoma, and absolute glaucoma);

disorders of the optic nerve or visual pathways, such as papilledema(choked disk), papillitis (optic neuritis), retrobulbar neuritis,ischemic optic neuropathy, toxic amblyopia, optic atrophy, higher visualpathway lesions, disorders of ocular motility (e.g., third cranial nervepalsies, fourth cranial nerve palsies, sixth cranial nerve palsies,internuclear ophthalmoplegia, and gaze palsies);

free radical induced eye disorders and diseases; and

immunologically-mediated eye disorders and diseases, such as Graves'ophthalmopathy, conical cornea, dystrophia epithelialis corneae, cornealleukoma, ocular pemphigus, Mooren's ulcer, scleritis, and sarcoidosis(See The Merck Manual, Sixteenth Edition, 217:2365-2397 (1992) and TheEye Book, Cassel, Billig, and Randall, The Johns Hopkins UniversityPress (1998)).

The compositions and methods of the present invention are also useful inthe treatment of the following non-limiting eye injuries, and symptomsand complications resulting therefrom: conjunctival and corneal foreignbody injuries, corneal abrasion, intraocular foreign body injuries,lacerations, lid lacerations, contusions, lid contusions (black eye),trauma to the globe, laceration of the iris, cataract, dislocated lens,glaucoma, vitreous hemorrhage, orbital-floor fractures, retinalhemorrhage or detachment, and rupture of the eyeball, anterior chamberhemorrhage (traumatic hyphema), burns, eyelid burns, chemical burns,chemical burns of the cornea and conjunctiva, and ultraviolet lightburns (sunburn). See The Merck Manual, Sixteenth Edition, 217:2364-2365(1992).

The compositions and methods of the present invention are also useful intreating and/or preventing the following non-limiting exemplary symptomsand complications of eye disease, eye disorder or eye injury:subconjunctival hemorrhages, vitreous hemorrhages, retinal hemorrhages,floaters, retinal detachments, photophobia, ocular pain, scotomas(negative and positive), errors of refraction, emmetropia, ametropia,hyperopia (farsightedness), myopia (nearsightedness), astigmatism,anisometropia, aniseikonia, presbyopia, bleeding, recurrent bleeding,sympathetic ophthalmia, inflammation, swelling, redness of the eye,irritation of the eye, corneal ulceration and scarring, iridocyclitis,perforation of the globe, lid deformities, exophthalmos, impairedmobility of the eye, lid swelling, chemosis, loss of vision, includingpartial or total blindness, optic neuritis, fever, malaise,thrombophlebitis, cavernous sinus thrombosis, panophthalmitis, infectionof the meninges and brain, papilledema, severe cerebral symptoms(headache, decreased level of consciousness, and convulsions), cranialnerve palsies, epiphora (chronic or persistent tearing), copious refluxof mucus or pus, follicular subconjunctival hyperplasia, cornealvascularization, cicatrization of the conjunctiva, cornea, and lids,pannus, hypopyon, lagophthalmos, phlyctenules, rubeosis iridis,bitemporal hemianopia, and homonymous hemianopia. See The Merck Manual,Sixteenth Edition, 217:2362-2363 (1992).

The derivative may be administered in combination with an effectiveamount of one or more factor(s) useful in treating vision disorder,improving vision, treating memory impairment, or enhancing memoryperformance.

In a preferred embodiment, the factor(s) to be combined with thederivative is/are selected from the group consisting ofimmunosuppressants for treating autoimmune, inflammatory, andimmunologically-mediated disorders; wound healing agents for treatingwounds resulting from injury or surgery; antiglaucomatous medicationsfor treating abnormally elevated intraocular pressure; neurotrophicfactors and growth factors for treating neurodegenerative disorders orstimulating neurite outgrowth; compounds effective in limiting orpreventing hemorrhage or neovascularization for treating maculardegeneration; and antioxidants for treating oxidative damage to eyetissues.

Pharmaceutical Compositions of the Present Invention

The present invention also relates to a pharmaceutical compositioncomprising:

(i) an effective amount of a derivative for treating a vision disorder,improving vision, treating memory impairment, or enhancing memoryperformance in an animal; and

(ii) a pharmaceutically acceptable carrier.

The derivative may be administered in combination with an effectiveamount of one or more factor(s) useful in treating vision disorders,improving vision, treating memory impairment, or enhancing memoryperformance.

N-linked Ureas and Carbamates of Heterocyclic Thioesters

The N-linked ureas and carbamates of heterocyclic thioesters used in themethods and pharmaceutical compositions of the present invention are lowmolecular weight, small molecule compounds having an affinity for anFKBP-type immunophilin, such as FKBP12. When an N-linked urea orcarbamate of a heterocyclic thioester binds to an FKBP-typeimmunophilin, it has been found to inhibit the prolylpeptidyl cis-transisomerase, or rotamase, activity of the binding protein. Unexpectedly,these compounds have also been found to stimulate hair growth. Thesecompounds are devoid of any significant immunosuppressive activity.

Formula I

The N-linked urea or carbamate of a heterocyclic thioester may be acompound of formula I

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein:

A and B, taken together with the nitrogen and carbon atoms to which theyare respectively attached, form a 5-7 membered saturated or unsaturatedheterocyclic ring containing, in addition to the nitrogen atom, one ormore additional O, S, SO, SO₂, N, NH, or NR₃ heteroatom(s);

X is either O or S;

Y is a direct bond, C₁-C₆ straight or branched chain alkyl, or C₂-C₆straight or branched chain alkenyl, wherein any carbon atom of saidalkyl or alkenyl is optionally substituted in one or more position(s)with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy,alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbonatom of said alkyl or alkenyl is optionally replaced with O, NH, NR₃, S,SO, or SO₂;

R₃ is selected from the group consisting of hydrogen, C₁-C₆ straight orbranched chain alkyl, C₃-C₆ straight or branched chain alkenyl oralkynyl, and C₁-C₄ bridging alkyl wherein a bridge is formed between thenitrogen and a carbon atom of said alkyl or alkenyl chain containingsaid heteroatom to form a ring, wherein said ring is optionally fused toan Ar group;

Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- orheterocyclic ring, wherein the ring is either unsubstituted orsubstituted with one or more substituent(s) independently selected fromthe group including, but not limited to, alkylamino, amido, amino,aminoalkyl, azo, benzyloxy, C₁-C₉ straight or branched chain alkyl,C₁-C₉ alkoxy, C₂-C₉ alkenyloxy, C₂-C₉ straight or branched chainalkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, carbonyl, carboxy, cyano,diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano,isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl,sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester,thioformamido, trifluoromethyl, and carboxylic and heterocyclicmoieties, including alicyclic and aromatic structures; wherein theindividual ring size is 5-8 members; wherein said heterocyclic ringcontains 1-6 heteroatom(s) independently selected from the groupconsisting of O, N, and S; and wherein said aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide;

Z is a direct bond, C₁-C₆ straight or branched chain alkyl, or C₂-C₆straight or branched chain alkenyl, wherein any carbon atom of saidalkyl or alkenyl is optionally substituted in one or more position(s)with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy,alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbonatom of said alkyl or alkenyl is optionally replaced with O, NH, NR₃, S,SO, or SO₂;

C and D are independently hydrogen, Ar, C₁-C₆ straight or branched chainalkyl, or C₂-C₆ straight or branched chain alkenyl; wherein said alkylor alkenyl is optionally substituted with one or more substituent(s)independently selected from the group consisting of C₃-C₈ cycloalkyl,C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein saidalkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substitutedwith C₁-C₆ alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, haloalkyl,thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, iminoalkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein anycarbon atom of said alkyl or alkenyl is optionally substituted in one ormore positions with oxygen to form a carbonyl; or wherein any carbonatom of said alkyl or alkenyl is optionally replaced with O, NH, NR₃, S,SO, or SO₂;

W is O or S; and

U is either O or N, provided that:

when U is O, then R₁ is a lone pair of electrons and R₂ is selected fromthe group consisting of Ar, C₃-C₈ cycloalkyl, C₁-C₆ straight or branchedchain alkyl, and C₂-C₆ straight or branched chain alkenyl, wherein saidalkyl or alkenyl is optionally substituted with one or moresubstituent(s) independently selected from the group consisting of Arand C₃-C₈ cycloalkyl; and

when U is N, then R₁ and R₂ are independently selected from the groupconsisting of hydrogen, Ar, C₃-C₈ cycloalkyl, C₁-C₆ straight or branchedchain alkyl, and C₂-C₆ straight or branched chain alkenyl, wherein saidalkyl or alkenyl is substituted with one or more substituent(s)independently selected from the group consisting of Ar and C₃-C₈cycloalkyl; or R₁ and R₂ are taken together to form a heterocyclic 5 or6 membered ring selected from the group consisting of pyrrolidine,imidazolidine, pyrazolidine, piperidine, and piperazine.

Useful carbo- and heterocyclic rings include without limitation phenyl,benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl,isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl,benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl,pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl,thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl,isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, andphenoxazinyl.

In a preferred embodiment of formula I, Ar is selected from the groupconsisting of phenyl, benzyl, naphthyl, indolyl, pyridyl, pyrrolyl,pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl, quinolinyl,isoquinolinyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl,thiazolyl, pyrazolyl, and thienyl.

In a more preferred embodiment of the compounds of formula I, theN-linked urea or carbamate of a heterocyclic thioester is the compoundGPI 1605, of the formula

Formula II

The N-linked urea or carbamate of a heterocyclic thioester may also be acompound of formula II

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein:

E, F, G and J are independently CH₂, O, S, SO, SO₂, NH, or NR₃;

X is either O or S;

Y is a direct bond, C₁-C₆ straight or branched chain alkyl, or C₂-C₆straight or branched chain alkenyl, wherein any carbon atom of saidalkyl or alkenyl is optionally substituted in one or more position(s)with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy,alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbonatom of said alkyl or alkenyl is optionally replaced with O, NH, NR₃, S,SO, or SO₂;

R₃ is selected from the group consisting of hydrogen, C₁-C₄ straight orbranched chain alkyl, C₃-C₄ straight or branched chain alkenyl oralkynyl, and C₁-C₄ bridging alkyl wherein a bridge is formed between thenitrogen and a carbon atom of said alkyl or alkenyl chain containingsaid heteroatom to form a ring, wherein said ring is optionally fused toan Ar group;

Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- orheterocyclic ring, wherein the ring is either unsubstituted orsubstituted with one or more substituent(s) independently selected fromthe group including, but not limited to, alkylamino, amido, amino,aminoalkyl, azo, benzyloxy, C₁-C₉ straight or branched chain alkyl,C₁-C₉ alkoxy, C₂-C₉ alkenyloxy, C₂-C₉ straight or branched chainalkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, carbonyl, carboxy, cyano,diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano,isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl,sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester,thioformamido, trifluoromethyl, and carboxylic and heterocyclicmoieties, including alicyclic and aromatic structures; wherein theindividual ring size is 5-8 members; wherein said heterocyclic ringcontains 1-6 heteroatom(s) independently selected from the groupconsisting of O, N, and S; and wherein said aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide;

Z is a direct bond, C₁-C₆ straight or branched chain alkyl, or C₂-C₆straight or branched chain alkenyl, wherein any carbon atom of saidalkyl or alkenyl is optionally substituted in one or more position(s)with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy,alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbonatom of said alkyl or alkenyl is optionally replaced with O, NH, NR₃, S,SO, or SO₂;

C and D are independently hydrogen, Ar, C₁-C₆ straight or branched chainalkyl, or C₂-C₆ straight or branched chain alkenyl; wherein said alkylor alkenyl is optionally substituted with one or more substituent(s)independently selected from the group consisting of C₃-C₈ cycloalkyl,C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein saidalkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substitutedwith C₁-C₆ alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, haloalkyl,thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino,alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein anycarbon atom of said alkyl or alkenyl is optionally substituted in one ormore position(s) with oxygen to form a carbonyl; or wherein any carbonatom of said alkyl or alkenyl is optionally replaced with O, NH, NR₃, S,SO, or SO₂;

W is O or S; and

U is either O or N, provided that:

when U is O, then R₁ is a lone pair of electrons and R₂ is selected fromthe group consisting of Ar, C₃-C₈ cycloalkyl, C₁-C₆ straight or branchedchain alkyl, and C₂-C₆ straight or branched chain alkenyl, wherein saidalkyl or alkenyl is optionally substituted with one or moresubstituent(s) independently selected from the group consisting of Arand C₃-C₈ cycloalkyl; and

when U is N, then R₁ and R₂ are independently selected from the groupconsisting of hydrogen, Ar, C₃-C₈ cycloalkyl, C₁-C₆ straight or branchedchain alkyl, and C₂-C₆ straight or branched chain alkenyl, wherein saidalkyl or alkenyl is optionally substituted with one or moresubstituent(s) independently selected from the group consisting of Arand C₃-C₈ cycloalkyl; or R₁ and R₂ are taken together to form aheterocyclic 5 or 6 membered ring selected from the group consisting ofpyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.

Useful carbo- and heterocyclic rings include without limitation phenyl,benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl,isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl,benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl,pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl,thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl,isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, andphenoxazinyl.

In a preferred embodiment of formula II, Ar is selected from the groupconsisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl,pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl,thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

Formula III

Additionally, the N-linked urea or carbamate of a heterocyclic thioestermay be a compound of formula III

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein:

E, F, and G are independently CH₂, O, S, SO, SO₂, NH, and NR₃;

X is either O or S;

Y is a direct bond, C₁-C₆ straight or branched chain alkyl, or C₂-C₆straight or branched chain alkenyl, wherein any carbon atom of saidalkyl or alkenyl is optionally substituted in one or more position (s)with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy,alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbonatom of said alkyl or alkenyl is optionally replaced with O, NH, NR₃, S,SO, or SO₂;

R₃ is selected from the group consisting of hydrogen, C₁-C₄ straight orbranched chain alkyl, C₃-C₄ straight or branched chain alkenyl oralkynyl, and C₁-C₄ bridging alkyl wherein a bridge is formed between thenitrogen and a carbon atom of said alkyl or alkenyl chain containingsaid heteroatom to form a ring, wherein said ring is optionally fused toan Ar group;

Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- orheterocyclic ring, wherein the ring is either unsubstituted orsubstituted with one or more substituent(s) independently selected fromthe group including, but not limited to, alkylamino, amido, amino,aminoalkyl, azo, benzyloxy, C₁-C₉ straight or branched chain alkyl,C₁-C₉ alkoxy, C₂-C₉ alkenyloxy, C₂-C₉ straight or branched chainalkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, carbonyl, carboxy, cyano,diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano,isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl,sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester,thioformamido, trifluoromethyl, and carboxylic and heterocyclicmoieties, including alicyclic and aromatic structures; wherein theindividual ring size is 5-8 members; wherein said heterocyclic ringcontains 1-6 heteroatom(s) independently selected from the groupconsisting of O, N, and S; and wherein said aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide;

Z is a direct bond, C₁-C₆ straight or branched chain alkyl, or C₂-C₆straight or branched chain alkenyl, wherein any carbon atom of saidalkyl or alkenyl is optionally substituted in one or more position(s)with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy,alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbonatom of said alkyl or alkenyl is optionally replaced with O, NH, NR₃, S,SO, or SO₂;

C and D are independently hydrogen, Ar, C₁-C₆ straight or branched chainalkyl, or C₂-C₆ straight or branched chain alkenyl; wherein said alkylor alkenyl is optionally substituted with one or more substituent(s)independently selected from the group consisting of C₃-C₈ cycloalkyl,C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein saidalkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substitutedwith c₁-C₆ alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, haloalkyl,thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino,alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein anycarbon atom of said alkyl or alkenyl is optionally substituted in one ormore position(s) with oxygen to form a carbonyl; or wherein any carbonatom of said alkyl or alkenyl is optionally replaced with O, NH, NR₃, S,SO, or SO₂;

W is O or S; and

U is either O or N, provided that:

when U is O, then R₁ is a lone pair of electrons and R₂ is selected fromthe group consisting of Ar, C₃-C₈ cycloalkyl, C₁-C₆ straight or branchedchain alkyl, and C₂-C₆ straight or branched chain alkenyl, wherein saidalkyl or alkenyl is optionally substituted with one or moresubstituent(s) independently selected from the group consisting of Arand C₃-C₈ cycloalkyl; and

when U is N, then R₁ and R₂ are independently selected from the groupconsisting of hydrogen, Ar, C₃-C₈ cycloalkyl, C₁-C₆ straight or branchedchain alkyl, and C₂-C₆ straight or branched chain alkenyl, wherein saidalkyl or alkenyl is optionally substituted with one or moresubstituent(s) independently selected from the group consisting of Arand C₃-C₈ cycloalkyl; or R₁ and R₂ are taken together to form aheterocyclic 5 or 6 membered ring selected from the group consisting ofpyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.

Useful carbo- and heterocyclic rings include without limitation phenyl,benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl,isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl,benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl,pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl,thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl,isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, andphenoxazinyl.

In a preferred embodiment of formula III, Ar is selected from the groupconsisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl,pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl,thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

In a more preferred embodiment of the compounds of formula III, theN-linked urea or carbamate of a heterocyclic thioester is the compoundGPI 1605, of the formula

Formula IV

The N-linked urea or carbamate of a heterocyclic thioester may furtherbe a compound of formula IV

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein:

n is 1, 2 or 3;

X is either O or S;

Y is a direct bond, C₁-C₆ straight or branched chain alkyl, or C₂-C₆straight or branched chain alkenyl, wherein any carbon atom of saidalkyl or alkenyl is optionally substituted in one or more position(s)with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy,alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbonatom of said alkyl or alkenyl is optionally replaced with O, NH, NR₃, S,SO, or SO₂;

R₃ is selected from the group consisting of hydrogen, C₁-C₄ straight orbranched chain alkyl, C₃-C₄ straight or branched chain alkenyl oralkynyl, and C₁-C₄ bridging alkyl wherein a bridge is formed between thenitrogen and a carbon atom of said alkyl or alkenyl chain containingsaid heteroatom to form a ring, wherein said ring is optionally fused toan Ar group;

Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- orheterocyclic ring, wherein the ring is either unsubstituted orsubstituted with one or more substituent(s) independently selected fromthe group including, but not limited to, alkylamino, amido, amino,aminoalkyl, azo, benzyloxy, C₁-C₉ straight or branched chain alkyl,C₁-C₉ alkoxy, C₂-C₉ alkenyloxy, C₂-C₉ straight or branched chainalkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, carbonyl, carboxy, cyano,diazo, ester, formanilido, halo, haloalkyl, hydroxy, imino, isocyano,isonitrilo, nitrilo, nitro, nitroso, phenoxy, sulfhydryl,sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano, thioester,thioformamido, trifluoromethyl, and carboxylic and heterocyclicmoieties, including alicyclic and aromatic structures; wherein theindividual ring size is 5-8 members; wherein said heterocyclic ringcontains 1-6 heteroatom(s) independently selected from the groupconsisting of O, N, and S; and wherein said aromatic or tertiary alkylamine is optionally oxidized to a corresponding N-oxide;

Z is a direct bond, C₁-C₆ straight or branched chain alkyl, or C₂-C₆straight or branched chain alkenyl, wherein any carbon atom of saidalkyl or alkenyl is optionally substituted in one or more position(s)with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy,alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbonatom of said alkyl or alkenyl is optionally replaced with O, NH, NR₃, S,SO, or SO₂;

C and D are independently hydrogen, Ar, C₁-C₆ straight or branched chainalkyl, or C₂-C₆ straight or branched chain alkenyl; wherein said alkylor alkenyl is optionally substituted with one or more substituent(s)independently selected from the group consisting of C₃-C₈ cycloalkyl,C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein saidalkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substitutedwith C₁-C₆ alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, haloalkyl,thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino,alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein anycarbon atom of said alkyl or alkenyl is optionally substituted in one ormore position(s) with oxygen to form a carbonyl; or wherein any carbonatom of said alkyl or alkenyl is optionally replaced with O, NH, NR₃, S,SO, or SO₂;

W is O or S; and

U is either O or N, provided that:

when U is O, then R₁ is a lone pair of electrons and R₂ is selected fromthe group consisting of Ar, C₃-C₈ cycloalkyl, C₁-C₆ straight or branchedchain alkyl, and C₂-C₆ straight or branched chain or alkenyl, whereinsaid alkyl or alkenyl is optionally substituted with one or moresubstituent(s) independently selected from the group consisting of Arand C₃-C₈ cycloalkyl; and

when U is N, then R₁ and R₂ are independently selected from the groupconsisting of hydrogen, Ar, C₃-C₈, cycloalkyl, C₁-C₆ straight orbranched chain alkyl, and C₂-C₆ straight or branched chain alkenyl,wherein said alkyl or alkenyl is optionally substituted with one or moresubstituent(s) independently selected from the group consisting of Arand C₃-C₈ cycloalkyl; or R₁ and R₂ are taken together to form aheterocyclic 5 or 6 membered ring selected from the group consisting ofpyrrolidine, imidazolidine, pyrazolidine, piperidine, and piperazine.

Useful carbo- and heterocyclic rings include without limitation phenyl,benzyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, indolyl,isoindolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl,benzimidazolyl, benzthiazolyl, tetrahydrofuranyl, tetrahydropyranyl,pyridyl, pyrrolyl, pyrrolidinyl, pyridinyl, pyrimidinyl, purinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinolizinyl, furyl,thiophenyl, imidazolyl, oxazolyl, benzoxazolyl, thiazolyl, isoxazolyl,isotriazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl, trithianyl, indolizinyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, thienyl, tetrahydroisoquinolinyl,cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, andphenoxazinyl.

In a preferred embodiment of formula IV, Ar is selected from the groupconsisting of phenyl, benzyl, naphthyl, pyrrolyl, pyrrolidinyl,pyridinyl, pyrimidinyl, purinyl, quinolinyl, isoquinolinyl, furyl,thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, and thienyl.

Exemplary compounds of formula IV are presented in TABLE A.

TABLE A

No. n W Y Z C D R₁ R₂ 1 1 O (CH₂)₂ CH 3-Pyridyl H H 2-Methylbutyl 2 1 O(CH₂)₂ CH 3-Pyridyl H H 1,1-dimethylpropyl 3 1 O (CH₂)₂ CH 4-Methoxy H H1,1-dimethylpropyl phenyl 4 1 O CH₂ CH Phenyl H H 1,1-dimethylpropyl 5 1S (CH₂)₂ CH 4-Methoxy H H Cyclohexyl phenyl 6 1 O (CH₂)₂ CH 3-Pyridyl HH Cyclohexyl 7 1 S (CH₂)₂ CH 3-Pyridyl H H Cyclohexyl 8 1 S (CH₂)₂ CH3-Pyridyl H H 1-Adamantyl 9 1 S (CH₂)₂ CH 3-Pyridyl H H1,1-dimethylpropyl 10 1 O (CH₂)₂ CH Phenyl Phenyl H 1,1-dimethylpropyl11 2 O (CH₂)₂ CH Phenyl H H 1,1-dimethylpropyl 12 2 O (CH₂)₂ CH Phenyl HH Phenyl 13 2 O Direct CH 2-Phenyl 2-Phenyl H Phenyl bond ethyl ethyl 142 O Direct CH 2-Phenyl 2-Phenyl H Cyclohexyl bond ethyl ethyl 15 2 SDirect CH 2-Phenyl 2-Phenyl H Cyclohexyl bond ethyl ethyl 16 2 O (CH₂)₂CH 4-Methoxy H H Cyclohexyl phenyl

The most preferred compounds of formula IV are selected from the groupconsisting of:

3-(3-Pyridyl)-1-propyl-2S-1-[(2-methylbutyl)carbamoyl]pyrrolidine-2-carboxylate;

3-(3-Pyridyl)-1-propyl-2S-1-[(1′,1′-Dimethylpropyl)carbamoyl]pyrrolidine-2-carboxylate;

3-(3-Pyridyl)-1-propyl-2S-1-[(cyclohexyl)thiocarbamoyl]pyrrolidine-2-carboxylate;and

pharmaceutically acceptable salts, esters, and solvates thereof.

Formula V

The N-linked urea or carbamate of a heterocyclic thioester may be acompound of formula V

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein:

V is C, N, or S;

Y is a direct bond, C₁-C₆ straight or branched chain alkyl, or C₂-C₆straight or branched chain alkenyl, wherein any carbon atom of saidalkyl or alkenyl is optionally substituted in one or more position(s)with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy,alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbonatom of said alkyl or alkenyl is optionally replaced with O, NH, NR₃, S,SO, or SO₂;

R₃ is selected from the group consisting of hydrogen, C₁-C₆ straight orbranched chain alkyl, C₃-C₆ straight or branched chain alkenyl oralkynyl, and C₁-C₄ bridging alkyl wherein a bridge is formed between thenitrogen and a carbon atom of said alkyl or alkenyl chain containingsaid heteroatom to form a ring, wherein said ring is optionally fused toan Ar group;

Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- orheterocyclic ring, wherein the ring is either unsubstituted orsubstituted with one or more substituent(s); wherein the individual ringsize is 5-8 members; wherein said heterocyclic ring contains 1-6heteroatom(s) independently selected from the group consisting of O, N,and S; and wherein said aromatic or tertiary alkyl amine is optionallyoxidized to a corresponding N-oxide;

Z is a direct bond, C₁-C₆ straight or branched chain alkyl, or C₂-C₆straight or branched chain alkenyl, wherein any carbon atom of saidalkyl or alkenyl is optionally substituted in one or more position(s)with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy,alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any carbonatom of said alkyl or alkenyl is optionally replaced with O, NH, NR₃, S,SO, or SO₂;

C and D are independently hydrogen, Ar, C₁-C₆ straight or branched chainalkyl, or C₂-C₆ straight or branched chain alkenyl; wherein said alkylor alkenyl is optionally substituted with one or more substituent(s)independently selected from the group consisting of C₃-C₈ cycloalkyl,C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar; wherein saidalkyl, alkenyl, cycloalkyl or cycloalkenyl is optionally substitutedwith C₁-C₆ alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, haloalkyl,thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino,alkylamino, aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein anycarbon atom of said alkyl or alkenyl is optionally substituted in one ormore position(s) with oxygen to form a carbonyl; or wherein any carbonatom of said alkyl or alkenyl is optionally replaced with O, NH, NR₃, S,SO, or SO₂; and

A, B, R1, R2, U, W, and X are as otherwise defined in formula I above.

All the compounds of Formulas I-V possess asymmetric centers and thuscan be produced as mixtures of stereoisomers or as individual R- andS-stereoisomers. The individual stereoisomers may be obtained by usingan optically active starting material, by resolving a racemic ornon-racemic mixture of an intermediate at some appropriate stage of thesynthesis, or by resolving the compounds of Formulas I-V. It isunderstood that the compounds of Formulas I-V encompass individualstereoisomers as well as mixtures (racemic and non-racemic) ofstereoisomers. Preferably, S-stereoisomers are used in thepharmaceutical compositions and methods of the present invention.

Synthesis of N-linked Ureas and Carbamates of Heterocyclic Thioesters

The compounds of formulas I to V may be readily prepared by standardtechniques of organic chemistry, utilizing the general synthetic pathwaydepicted below. As described by Scheme I, cyclic amino acids 1 protectedby suitable blocking groups P on the amino acid nitrogen may be reactedwith thiols RSH to generate thioesters 2. After removal of theprotecting group, the free amine 3 may be reacted with a variety ofisocyanates or isothiocyanates to provide the final ureas or thioureas,respectively.

Isocyanates (R′NCO) or isothiocyanates (R′NCS) 4 may be convenientlyprepared from the corresponding readily available amines by reactionwith phosgene or thiophosgene, as depicted in Scheme II.

Thiols R-SH may be conveniently prepared from the corresponding readilyavailable alcohols or halides via a two step replacement of halide bysulfur, as described in Scheme III. Halides may be reacted withthiourea, and the corresponding alkyl thiouronium salts hydrolyzed toprovide thiols RSH. If alcohols are used as the starting materials, theymay be first converted to the corresponding halides by standard methods.

Affinity for FKBP12

The compounds used in the inventive methods and pharmaceuticalcompositions have an affinity for the FK506 binding protein,particularly FKBP12. The inhibition of the prolyl peptidyl cis-transisomerase activity of FKBP may be measured as an indicator of thisaffinity.

K_(i) Test Procedure

Inhibition of the peptidyl-prolyl isomerase (rotamase) activity of thecompounds used in the inventive methods and pharmaceutical compositionscan be evaluated by known methods described in the literature (Hardinget al., Nature, 1989, 341:758-760; Holt et al. J. Am. Chem. Soc.,115:9923-9938). These values are obtained as apparent K_(i)'s and arepresented for representative compounds in TABLE II.

The cis-trans isomerization of an alanine-proline bond in a modelsubstrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, is monitoredspectrophotometrically in a chymotrypsin-coupled assay, which releasespara-nitroanilide from the trans form of the substrate. The inhibitionof this reaction caused by the addition of different concentrations ofinhibitor is determined, and the data is analyzed as a change infirst-order rate constant as a function of inhibitor concentration toyield the apparent K_(i) values.

In a plastic cuvette are added 950 mL of ice cold assay buffer (25 mMHEPES, pH 7.8, 100 mM NaCl), 10 mL of FKBP (2.5 mM in 10 mM Tris-Cl pH7.5, 100 mM NaCl, 1 mM dithiothreitol), 25 mL of chymotrypsin (50 mg/mlin 1 mM HCl) and 10 mL of test compound at various concentrations indimethyl sulfoxide. The reaction is initiated by the addition of 5 mL ofsubstrate (succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg/mL in 2.35mM LiCl in trifluoroethanol).

The absorbance at 390 nm versus time is monitored for 90 seconds using aspectrophotometer and the rate constants are determined from theabsorbance versus time data files.

TABLE II In Vitro Test Results - Formulas I to V Compound K_(i) (nM) 1+++ 2 ++ 3 ++ 4 ++ 5 ++ 6 + 7 ++ 8 +++ 9 +++ 10 +++ 11 ++ 12 +++ 13 +++14 +++ 15 +++ 16 ++

Relative potencies of compounds are ranked according to the followingscale: ++++ denotes K_(i) or ED50<1 nM; +++ denotes K_(i) or ED50 of1-50 nM; ++ denotes K_(i) or ED 50 of 51-200 nM; + denotes K_(i) or EDof 201-500 nM.

Route of Administration

To effectively treat vision loss or promote vision regeneration, thecompounds used in the inventive methods and pharmaceutical compositionsmust readily affect the targeted areas. For these purposes, thecompounds are preferably administered [topically to the skin.]

Other routes of administration known in the pharmaceutical art are alsocontemplated by this invention.

Dosage

Dosage levels an the order of about 0.1 mg to about 10,000 mg of theactive ingredient compound are useful in the treatment of the aboveconditions, with preferred levels of about 0.1 mg to about 1,000 mg. Thespecific dose level for any particular patient will vary depending upona variety of factors, including the activity of the specific compoundemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration; the rate of excretion; drugcombination; the severity of the particular disease being treated; andthe form of administration. Typically, in vitro dosage-effect resultsprovide useful guidance on the proper doses for patient administration.Studies in animal models are also helpful. The considerations fordetermining the proper dose levels are well known in the art.

The compounds can be administered with other agents for treating visionloss, preventing vision degeneration, or promoting vision regeneration.Specific dose levels for such other agents will depend upon the factorspreviously stated and the effectiveness of the drug combination.

EXAMPLES

The following examples are illustrative of the present invention and arenot intended to be limitations thereon. Unless otherwise indicated, allpercentages are based upon 100% by weight of the final composition.

Example 1 Synthesis of 3-(3-Pyridyl)-1-propylmercaptyl2S-1-[(2-methylbutyl)carbamoyl]pyrrolidine-2-carboxylate (1)

3-(3-Pyridyl)-1-propylchloride

To a solution of 3-(3-pyridyl)-1-propanol (10 g; 72.4 mmol) inchloroform (100 mL) was added dropwise a solution of thionyl chloride(12.9 g; 108.6 mmol) in chloroform (50 mL). The resulting mixture wasrefluxed for 1 hour, then poured into ice-cold 50% aqueous potassiumhydroxide (150 mL). The layers were separated, and the organic phase wasdried, concentrated, and purified on a silica gel column, eluting with40% ethylacetate in hexane, to obtain 10 g (65%) of the chloride as aclear oil. ¹H NMR (300 MHz, CDCl₃): δ2.02-2.11 (m, 2H); 2.77 (m, 2H);3.51 (m, 2H); 7.20 (m, 1H); 7.49 (m, 1H); 8.45 (m, 2H).

3-(3-Pyridyl)-1-propylmercaptan

A mixture of 3-(3-pyridyl)-1-propylchloride (3 g; 19.4 mmol) andthiourea (1.48 g; 19.4 mmol) in ethanol (10 mL) was refluxed for 24hours. Aqueous sodium hydroxide, 15 mL of a 0.75 N solution, was added,and the mixture was refluxed for an additional 2 hours. After cooling toroom temperature, the solvent was removed in vacuo. Chromatographicpurification of the crude thiol on a silica gel column eluting with 50%ethyl acetate in hexane delivered 1.2 g of3-(3-Pyridyl)-1-propylmercaptan as a clear liquid. ¹H NMR (300 MHz,CDCl₃): δ1.34 (m, 1H); 1.90 (m, 2H); 2.52 (m, 2H); 2.71 (m, 2H); 7.81(m, 1H); 7.47 (m, 1H); 8.42 (m, 2H).

3-(3-Pyridyl)-1-propylmercaptylN-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate

A mixture of N-(tert-butyloxycarbonyl)-(S)-proline (3.0 g; 13.9 mmol);3-(3-Pyridyl)-1-propylmercaptan (3.20 g; 20.9 mmol),dicyclohexylcarbodiimide (4.59 g; 22.24 mmol), camphorsulfonic acid(1.08 g; 4.63 mmol), and 4-dimethylaminopyridine (0.60 g; 4.63 mmol) indry methylene chloride (100 mL) was stirred overnight. The reactionmixture was diluted with methylene chloride (50 mL) and water (100 mL),and the layers were separated. The organic phase was washed with water(3×100 mL), dried over magnesium sulfate, and concentrated, and thecrude residue was purified on a silica gel column eluting with ethylacetate to obtain 4.60 g (95%) of the thioester as a thick oil. ¹H NMR(300 MHz, CDCl₃): δ1.45 (s, 9H); 1.70-2.05 (m, 5H); 2.32 (m, 1H); 2.71(t, 2H); 2.85 (m, 2H); 3.50 (m, 2H); 4.18 (m, 1H); 7.24 (m, 1H); 7.51(m, 1H); 8.48 (m, 2H).

3-(3-Pyridyl)-1-propylmercaptyl pyrrolidine-2-carboxylate

A solution of 3-(3-Pyridyl)-1-mercaptylN-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate (4.60 g; 13.1 mmol)in methylene chloride (60 mL) and trifluoroacetic acid (6 mL) wasstirred at room temperature for three hours. Saturated potassiumcarbonate was added until the pH was basic, and the reaction mixture wasextracted with methylene chloride (3×). The combined organic extractswere dried and concentrated to yield 2.36 g (75%) of the free amine as athick oil. ¹H NMR (300 MHz, CDCl₃): δ1.87-2.20 (m, 6H); 2.79 (m, 2H);3.03-3.15 (m, 4H total); 3.84 (m, 1H); 7.32 (m, 1H); 7.60 (m, 1H); 8.57(m, 2H).

3-(3-Pyridyl)-1-propylmercaptyl2S-1-[(2-methylbutyl)carbamoyl]pyrrolidine-2-carboxylate (1)

A solution of 2-methylbutylamine (113 mg; 1.3 mmol) and triethylamine(132 mg; 1.3 mmol) in methylene (chloride (5 mL) was added to a solutionof triphosgene (128 mg; 0.43 mmol) in methylene chloride (5 mL). Theresulting mixture was refluxed for 1 hour and then cooled to roomtemperature. 3-(3-Pyridyl)-1-propylmercaptyl pyrrolidine-2-carboxylate(300 mg; 1.3 mmol) in 5 mL of methylene chloride was added and theresulting mixture was stirred for 1 hour and then partitioned betweenwater and a 1:1 mixture of ethyl acetate and hexane. The organic phasewas dried, concentrated and purified by column chromatography (50% ethylacetate/hexane) to obtain 250 mg (55%) of the compound of Example 1(Compound 1, Table II) as an oil. ¹H NMR (300 MHz, CDCl₃): d ¹H NMR(CDCl₃, 300 MHz): δ0.89-0.93 (m, 6H); 1.10-1.20 (m, 1H); 1.27 (s, 1H);1.36-1.60 (m, 2H); 1.72 (s, 2H); 1.97-2.28 (m, 6H); 2.70-2.75 (m, 2H);2.92-3.54 (m, 6H); 4.45-4.47 (m, 1H); 7.21-7.29 (m, 1H); 7.53-7.56 (dd,1H); 8.46-8.48 (s, 2H).

Example 2 Synthesis of 3-(3-Pyridyl)-1-propyl2S-1-[(1′,1′-Dimethylpropyl)carbamoyl]pyrrolidine-2-carboxylate (2)

Reaction of 3-(3-pyridyl)-1-propylmercaptyl pyrrolidine-2-carboxylatewith the isocyanate, generated from tert-amylamine and triphosgene, asdescribed for Example 1, provided the compound of Example 2 (Compound 2,Table II) in 62% yield. ¹H NMR (CDCl₃, 300 MHz): δ0.83 (t, 3H); 1.27 (s,6H); 1.64-1.71 (m, 2H); 1.91-2.02 (m, 7H); 2.66-2.71 (t, 2H); 2.85 (m,2H); 3.29-3.42 (m, 2H); 4.11 (br, 1H); 4.37-4.41 (m, 1H).

Example 3 Synthesis of 3-(3-pyridyl)-1-propylmercaptyl2S-1-[(cyclohexyl)thiocarbamoyl]-pyrrolidine-2-carboxylate (7)

A mixture of cyclohexylisothiocyanate (120 mg; 0.9 mmol),3-(3-pyridyl)-1-propylmercaptyl pyrrolidine-2-carboxylate (200 mg; 0.9mmol) and triethylamine (90 mg; 0.9 mmol) in 20 mL of methylene chloridewas stirred for 1 hour and then partitioned between water and a 1:1mixture of ethyl acetate and hexane. The organic phase was dried,concentrated and purified by column chromatography (50% ethylacetate/hexane) to obtain 160 mg (47%) of the compound of Example 3(Compound 7, Table II). ¹H NMR (CDCl₃, 300 MHz): δ1.16-1.40 (m, 6H);1.50-1.71 (m, 4H); 1.95-2.08 (m, 7H); 2.70-2.75 (t, 2H); 3.03 (m, 2H);3.40-3.60 (m, 2H); 4.95-4.98 (d, 1H); 5.26-5.29 (d, 1H); 7.17-7.25, (m,1H).

Example 4 Synthesis of 3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate (1)

Methyl (2S)-1-(1,2-dioxo-2-methoxyethyl)-2-pyrrolidinecarboxylate

A solution of L-proline methyl ester hydrochloride (3.08 g; 18.60 mmol)in dry methylene chloride was cooled to 0° C. and treated withtriethylamine (3.92 g; 38.74 mmol; 2.1 eq). After stirring the formedslurry under a nitrogen atmosphere for 15 min, a solution of methyloxalyl chloride (3.20 g; 26.12 mmol) in methylene chloride (45 ml) wasadded dropwise. The resulting mixture was stirred at 0° C. for 1.5 hour.After filtering to remove solids, the organic phase was washed withwater, dried over MgSO₄ and concentrated. The crude residue was purifiedon a silica gel column, eluting with 50% ethyl acetate in hexane, toobtain 3.52 g (88%) of the product as a reddish oil. Mixture ofcis-trans amide rotamers; data for trans rotamer given. ¹H NMR (CDCl₃):d 1.93 (dm, 2H); 2.17 (m, 2H); 3.62 (m, 2H); 3.71 (s, 3H); 3.79, 3.84(s, 3H total); 4.86 (dd, 1H, J=8.4, 3.3).

Methyl (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate

A solution of methyl(2S)-1-(1,2-dioxo-2-methoxyethyl)-2-pyrrolidinecarboxylate (2.35 g;10.90 mmol) in 30 ml of tetrahydrofuran (THF) was cooled to −78° C. andtreated with 14.2 ml of a 1.0 M solution of 1,1-dimethylpropylmagnesiumchloride in THF. After stirring the resulting homogeneous mixture at−78° C. for three hours, the mixture was poured into saturated ammoniumchloride (100 ml) and extracted into ethyl acetate. The organic phasewas washed with water, dried, and concentrated, and the crude materialobtained upon removal of the solvent was purified on a silica gelcolumn, eluting with 25% ethyl acetate in hexane, to obtain 2.10 g (75%)of the oxamate as a colorless oil. ¹H NMR (CDCl₃): d 0.88 (t, 3H); 1.22,1.26 (s, 3H each); 1.75 (dm, 2H); 1.87-2.10 (m, 3H); 2.23 (m, 1H); 3.54(m, 2H); 3.76 (s, 3H); 4.52 (dm, 1H, J=8.4, 3.4).

Synthesis of(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylic acid

A mixture of methyl(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate (2.10 g;8.23 mmol), 1 N LiOH (15 ml), and methanol (50 ml) was stirred at 0° C.for 30 minutes and at room temperature overnight. The mixture wasacidified to pH 1 with 1 N HCl, diluted with water, and extracted into100 ml of methylene chloride. The organic extract was washed with brineand concentrated to deliver 1.73 g (87%) of snow-white solid which didnot require further purification. ¹H NMR (CDCl₃): d 0.87 (t, 3H); 1.22,1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H); 2.25 (m,1H); 3.53 (dd, 2H, J=10.4, 7.3); 4.55 (dd, 1H, J=8.6, 4.1).

3-Phenyl-1-propyl (2S)-1-(3,3-dimethyl-12-dioxopentyl)-2-pyrrolidinecarboxylate (1)

A mixture of(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidine-carboxylic acid (600mg; 2.49 mmol), 3-phenyl-1-propanol (508 mg; 3.73 mmol),dicyclohexylcarbodiimide (822 mg; 3.98 mmol), camphorsulfonic acid (190mg; 0.8 mmol) and 4-dimethylaminopyridine (100 mg; 0.8 mmol) inmethylene chloride (20 ml) was stirred overnight under a nitrogenatmosphere. The reaction mixture was filtered through Celite to removesolids and concentrated in vacuo, and the crude material was purified ona flash column (25% ethyl acetate in hexane) to obtain 720 mg (80%) ofExample 1 as a colorless oil. ¹H NMR (CDCl₃): d 0.84 (t, 3H); 1.19 (s,3H); 1.23 (s, 3H); 1.70 (dm, 2H); 1.98 (m, 5H); 2.22 (m, 1H); 2.64 (m,2H); 3.47 (m, 2H); 4.14 (m, 2H); 4.51 (d, 1H); 7.16 (m, 3H); 7.26 (m,2H).

FIG. 1. GPI 1046 Protects Retinal Ganglion Cells Against DegenerationFollowing Retinal Ischemia

Retinal ganglion cells were retrogradely labeled in adult rats bybilateral injection of fluorogold in their lateral geniculate nuclei.Labeled ganglion cells in the normal rat retina appear as white profilesagainst the dark background (FIG. 1A). Complete retinal ischemia wasproduced by infusing normal saline solution into the retinal vitreouscavity of each eye until the intraocular pressure exceeded arterialblood pressure. 28 days after the ischemic episode extensivedegeneration of retinal ganglion cell was evidenced by massive reductionin the density of fluorogold labeled cells (FIG. 1B). Administration ofGPI 1046 10 mg/kg, s.c.) 1 hour prior to the ischemic episode and at 10mg/kg/day for the next four days produced noticeable protection of alarge proportion of the vulnerable ganglion cell population (FIG. 1C).

FIG. 2. GPI 1046 Prevents Degeneration of Optic Nerve Axons and MyelinFollowing Retinal Ischemia

Examination of the optic nerves from the same retinal ischemia casesreveals that GPI 1046 produces dramatic protection of optic nerveelement from ischemic degeneration. Toluidine blue staining of eponembedded optic nerve cross sections revealed the detail of myelinsheaths (white circles) and optic nerve axons (black centers) in thenormal rat optic nerve. Optic nerves from vehicle treated cases examined28 days after a 1 hour retinal ischemic episode are characterized by adecreased density of optic nerve axons and the appearance of numerousdegenerating myelin figures (bright white filled circles). Treatmentwith GPI 1046 protected the majority of optic nerve axons fromdegeneration and also dramatically decreased the density of degeneratingmyelin figures.

FIG. 3. GPI 1046 Provides Moderate Protection Against Retinal GanglionCell Death After Optic Nerve Transection

Complete transection of the optic nerve 5 mm from the eyeball producesmassive degeneration of retinal ganglion cells, representing lossof >87% of the normal ganglion cell population 90 days after the injury(Table 1). Few spared fluorogold pre labeled ganglion cells are presentin vehicle treated cases (large white figures) among a population ofsmall microglia that digest the debris of the degenerating cells andtake up the fluorogold label (FIG. 3A). Treatment with GPI 1046 for 14days resulted in a small but not significant increase in the density ofretinal ganglion cells that survived 90 days after transection (Table 1)but treatment with GPI 1046 for the first 28 days after transectionproduced moderate but significant protection of 12.6% of the vulnerableganglion cell population (Table 1, FIG. 3B).

FIG. 4. GPI 1046 Treatment Duration Significantly Affects the Process ofOptic Nerve Axonal Degeneration After Transection

Examination of optic nerve axon density in the proximal stump of theoptic nerve from the same cases revealed a more dramatic protectionafforded by GPI 1046 treatment. 90 days after transection few ganglioncell axons remain within the optic nerve (FIG. 4B), representing only5.6% of the normal population. The loss of axons reflects both the deathof retinal ganglion cells and the regression or “dying back” of theaxons of ˜70% of the small surviving ganglion cell population into theretina itself (Table 1). Treatment with GPI 1046 for the first 14 daysafter optic nerve transection produced a small but significant 5.3%protection of optic nerve axons (FIG. 4D, Table 1), but treatment withthe same dose of GPI 1046 for 28 days resulted in the protection ofoptic nerve axons for the vast majority (81.4%) of spared retinalganglion cells (FIG. 4C, Table 1).

FIG. 5. GPI 1046 Treatment Produces a Greater Effect on Optic NerveAxons than Ganglion Cell Bodies

This summary figure shows data from FIG. 3 ganglion cell protection andhigher power photomicrographs of optic nerve axon protection (FIG. 5A&B,upper panels). 28 day treatment with GPI 1046 produced a significantincrease in the density of large, and particularly medium and smallcaliber optic nerve axons (FIG. 5C&D, lower panels).

FIG. 6. GPI 1046 Treatment for 28 Days After Optic Nerve TransectionPrevents Myelin Degeneration in the Proximal Stump

Myelin basic protein immunohistochemistry labels fascicles (darkerlabeled ‘islands’) of myelinated axons in the normal optic nerve (FIG.6A, upper left). 90 days after transection extensive degeneration ofmyelin is evident in vehicle treated cases, characterized by the loss offascicular organization and the appearance of numerous large densedegenerating myelin figures (FIG. 6B, upper right). Treatment with GPI1046 for the first 14 days after optic nerve transection did not alterthe pattern of myelin degeneration (FIG. 6C, lower left panel), andyielded an insignificant 1.6% quantitative recovery in myelin density(Table 1). Extending the GPI 1046 treatment course through the first 28days after optic nerve transection produced a dramatic preservation ofthe fascicular staining pattern for myelin basic protein in the proximalstump of the optic nerve and decreased the density of degeneratingmyelin figures (FIG. 6D, lower right panel), representing a 70% recoveryof myelin density (Table 1).

FIG. 7. FKBP-12 Immunohistochemistry Labels Oligodendroglia (Large DarkCells with Fibrous Processes), the Cells Which Produce Myelin, LocatedBetween the Fascicles of Optic Nerve Fibers, and Also Some Optic NerveAxons

FIG. 8. GPI 1046 Treatment for 28 Days After Optic Nerve TransectionPrevents Myelin Degeneration in the Distal Stump

Complete transection of the optic nerve leads to degeneration of thedistal segments (axon fragments disconnected from the ganglion cellbodies), and the degeneration of their myelin sheaths. 90 days aftertransection (FIG. 8B) myelin basic protein immunohistochemistry revealsthe near total loss of fascicular organization (present in the normaloptic nerve, FIG. 8A) and the presence of numerous dense degeneratingmyelin figures. Quantitation reveals that the cross sectional area ofthe transected distal stump shrinks by 31% and loses approximately ½ ofits myelin (Table 1). Treatment with GPI 1046 for the first 14 daysafter transection did not protect against shrinkage of the distal stumpbut did slightly increase the density of myelin, though the density ofdegenerating myelin figures remained high (FIG. 8C, Table 1). GPI 1046treatment through the first 28 days produced dramatic protection of thefascicular pattern of myelin labeling, decreased the density ofdegenerating myelin figures, prevented cross sectional shrinkage of thedistal stump of the transected nerve and maintained the myelin levels at˜99% of normal levels (FIG. 8D, Table 1).

FIG. 9. 28 Day Treatment with GPI 1046 Treatment Beginning 8 Weeks AfterOnset of Streptozotocin Induced Diabetes Decreases the Extent ofNeovascularization in the Inner and Outer Retina and Protects Neurons inthe Inner Nuclear Layer (INL) and Ganglion Cell Layer (GCL) fromDegeneration

Negative images of cresyl violet stained tangential retinal sectionsreveals perikarya in the three cellular layers (FIG. 9A). The retinae ofstreptozotocin treated animals administered only vehicle (FIG. 9B)exhibited loss of cells from the ONL and INL, decreased thickness of theOuter plexiform layer (the dark area between ONL and INL) and a dramaticincrease in the size and density of retinal blood vessels (large blackcircular outlines) in the INL, OPL, ONL and the photoreceptor layer (PR,the gray fuzzy area above the ONL). GPI 1046 treatment reducedneovascularization (i.e. prevented the proliferation of blood vessels)in the PR, ONL, OPL and INL. Although GPI 1046 did not appear to protectagainst neuronal loss in the ONL, it appeared to decrease the loss ofneurons in both the INL and GCL compared to streptozotocin/vehicletreated controls.

Example 5 In Vivo Retinal Ganglion Cell and Optic Nerve Axon Tests

The extent of degeneration reduction or prevention in retinal ganglioncells and optic nerve axons was determined in a vision loss modelutilizing surgical optic nerve transection to simulate mechanical damageto the optic nerve. The effects of several neuroimmunophilin FKBPligands on retinal ganglion cells neuroprotection and optic nerve axondensity was determined experimentally, comparing 14 day and 28 dayneuroimmunophilin FKBP ligand treatments. The effects of treatment withneuroimmunophilin FKBP ligands on retinal ganglion cells and optic nerveaxons was correlated.

Surgical Procedures

Adult male Sprague Dawley rats (3 months old, 225-250 grams) wereanesthetized with a ketamine (87 mg/kg) and xylazine (13 mg/kg) mixture.Retinal ganglion cells were pre-labeled by bilateral stereotaxicinjection of the fluorescent retrogradely transported marker fluoro-gold(FG, 0.5 microliters of 2.5% solution in saline) at the coordinates ofthe LGNd (4.5 millimeters post β, 3.5 millimeters lateral, 4.6millimeters below dura). Four days later, FG labeled rats underwent asecond surgery for microsurgical bilateral intraorbital optic nervetransection 4-5 millimeters behind the orbit.

Experimental animals were divided into six experimental groups of sixrats (12 eyes) per group. One group received a neuroimmunophilin FKBPligand (10 milligrams per kg per day sc in PEG vehicle (20 percentpropylene glycol, 20 percent ethanol, and 60 percent saline)) for 14days. A second group received the same neuroimmunophilin FKBP liganddose for 28 days. Each treated group had a corresponding sham/surgeryand transection control group which received corresponding 14 or 28 daydosing with the vehicle only.

All animals were sacrificed 90 days after optic nerve transection andperfused pericardially with formalin. All eyes and optic nerves stumpswere removed. Cases were excluded from the study if the optic nervevasculature was damaged or if FG labeling was absent in the retina.

Retinal Ganglion Cell Counts

Retinas were removed from eyes and prepared for wholemount analysis. Foreach group, five eyes with dense and intense FG labeling were selectedfor quantitative analysis using a 20 power objective. Digital imageswere obtained from five fields in the central retina (3-4 millimetersradial to optic nerve head). FG labeled Large (>18 μm), medium (12-16μm), and small (<10 μm) ganglion cells and microglia were counted infive 400 μm by 400 μm fields per case, 5 cases per group.

Examination of Optic Nerves

Proximal and distal optic nerve stumps were identified, measured, andtransferred to 30% sucrose saline. The proximal stumps of five nerveswere blocked and affixed to a chuck, and 10 micron cross sections werecut on a cryostat; one in ten sections were saved per set. Sectionsincluding the region 1-2 mm behind the orbit were reacted for RT97neurofilament immunohistochemistry. Analysis of optic nerve axon densitywas performed using a 63 power oil immersion lens, a Dage 81 camera, andthe Simple Image Analysis program. RT97 positive optic nerve axons werecounted in three 200 μm by 200 μm fields per nerve. The area of thenerve was also determined for each case at 10 power.

As depicted graphically in Table I&II, the 14 day course of treatmentwith a neuroimmunophilin FKBP ligand provided moderate neuroprotectionof retinal ganglion cells observed 28 days after optic nervetransection. However, by 90 days after transection, only 5% of theganglion cell population remained viable.

90 days after optic nerve transection the number of axons persisting inthe proximal stump of the optic nerve represented approximately one halfof the number of surviving ganglion cells in groups of animals thatreceived vehicle alone or the 14 day course of treatment with aneuroimmunophilin FKBP ligand. These results indicate that over half ofthe transected ganglion cell axons retract beyond the optic nerve head,and that treatment with a neuroimmunophilin FKBP ligand during the first14 days after optic nerve transection is not sufficient to arrest thisretraction.

As depicted graphically in Table I&II, more prolonged treatment with aneuroimmunophilin FKBP ligand during the 28 day course of treatmentproduced a moderate increase in retinal ganglion cell neuroprotection.Approximately 12% of the vulnerable retinal ganglion cell population wasprotected. A

TABLE 1 Effect of prolonged GPI 1046 treatment on retinal ganglion cellsurvival, optic nerve axon perservation, and myelination 90 days afteroptic nerve transection ON head % Proximal optic Distat optic ON area %increased Spared surviving nerve myelin nerve myclin RGC Axon (% RGCs ONaxon RGC ON axon RGCs with basic protein basic protein GROUP Counts¹density² sham) Rescued density³ population Count⁴ ON axons Density⁵Density⁶ Sham 290 ± 14.8 7600* 100% — 120,000* 120,000 100% normalONT/Vehicle 35.9 ± 2.8 428 ± 68% (87% 14,855 4593 30.9% 52 + 5.2 SEM 31%shrinkage 34 loss) % loss 52.3% loss ONT/14 days 49 ± 5.3 569 ± 76% 5.3%1.5X 20,275 6820 33.6% 1.6 ± 3.0 SEM 33% shrinkage GPI 1046 23 %recovery 47% loss ONT/28 days 67.9 + 5.8* 1526 ± 95%* 12.6%* 5.0 X28,096* 22,861* 81.4% 70 ± 63 SEM 56% less shrinkage* GPI 1046 120* %recovery* 99% myclin preservation* *significance p < .001 ¹Meandensity + SEM of Fluoro-gold labeled retinal ganglion cells (RGC) in 400μm × 400 μm sample gridfields. ²mean density + SEM of RT97 neurofilamentantibody labeled optic nerve (ON) axons in 200 μm × 200 μm region ofinterest *estimate for 200 μm × 200 μm region in normal optic neverassuming 120,000 RGC axons in normal rat optic nerve, measured to be0.630 mm² mean cross sectional area ³adjusted for optic nerve diameter⁴calculated by multiplying axonal density by ON area ⁵ determined from20X analysis of % areal coverage of optic nerve cross section ⁶shrinkagedetermined by comparing cross sectional area to sham control, myelinleves determined by multiplying cross sectional area by myelin density

TABLE II

similar proportion (˜50%) of optic nerve axon density sparing was alsoobserved. These results demonstrate the startling result that extendingthe duration of treatment with a neuroimmunophilin FKBP ligands to 28days after transection completely arrests the regression of damagedaxons for essentially the entire surviving population of retinalganglion cells.

Additional results are set forth in Tables III & IV.

TABLE III

TABLE IV

Example 6

A patient is suffering from macular degeneration. A derivative asidentified above, alone or in combination with one or more other neopsicfactors, or a pharmaceutical composition comprising the same, may beadministered to the patient. A reduction in vision loss, prevention ofvision degeneration, and/or promotion of vision regeneration are/isexpected to occur following treatment.

Example 7

A patient is suffering from glaucoma, resulting in cupping of the opticnerve disc and damage to nerve fibers. A derivative as identified above,alone or in combination with one or more other neopsic factors, or apharmaceutical composition comprising the same, may be administered tothe patient. A reduction in vision loss, prevention of visiondegeneration, and/or promotion of vision regeneration are/is expected tooccur following treatment.

Example 8

A patient is suffering from cataracts requiring surgery. Followingsurgery, a derivative as identified above, alone or in combination withone or more other neopsic factors, or a pharmaceutical compositioncomprising the same, may be administered to the patient. A reduction invision loss, prevention of vision degeneration, and/or promotion ofvision regeneration are/is expected to occur following treatment.

Example 9

A patient is suffering from an impairment or blockage of retinal bloodsupply relating to diabetic retinopathy, ischemic optic neuropathy, orretinal artery or vein blockage. A derivative as identified above, aloneor in combination with one or more other neopsic factors, or apharmaceutical composition comprising the same, may be administered tothe patient. A reduction in vision loss, prevention of visiondegeneration, and/or promotion of vision regeneration are/is expected tooccur following treatment.

Example 10

A patient is suffering from a detached retina. A derivative asidentified above, alone or in combination with one or more other neopsicfactors, or a pharmaceutical composition comprising the same, may beadministered to the patient. A reduction in vision loss, prevention ofvision degeneration, and/or promotion of vision regeneration are/isexpected to occur following treatment.

Example 11

A patient is suffering from tissue damage caused by inflammationassociated with uveitis or conjunctivitis. A derivative as identifiedabove, alone or in combination with one or more other neopsic factors,or a pharmaceutical composition comprising the same may be administeredto the patient. A reduction in vision loss, prevention of visiondegeneration, and/or promotion of vision regeneration are/is expected tooccur following treatment.

Example 12

A patient is suffering from photoreceptor damage caused by chronic oracute exposure to ultraviolet light. A derivative as identified above,alone or in combination with one or more other neopsic factors, or apharmaceutical composition comprising the same, may be administered tothe patient. A reduction in vision loss, prevention of visiondegeneration, and/or promotion of vision regeneration are/is expected tooccur following treatment.

Example 13

A patient is suffering from optic neuritis. A derivative as identifiedabove, alone or in combination with one or more other neopsic factors,or a pharmaceutical composition comprising the same, may be administeredto the patient. A reduction in vision loss, prevention of visiondegeneration, and/or promotion of vision regeneration are/is expected tooccur following treatment.

Example 14

A patient is suffering from tissue damage associated with a “dry eye”disorder. A derivative as identified above, alone or in combination withone or more other neopsic factors, or a pharmaceutical compositioncomprising the same, may be administered to the patient. A reduction invision loss, prevention of vision degeneration, and/or promotion ofvision regeneration are/is expected to occur following treatment.

Example 15

Efficacy of representative compounds from different immunophilin ligandseries in protecting retinal ganglion cell axons from degenerationfollowing optic nerve transection is set forth in Table V.

Efficacy of representative compounds from different immunophilin ligandseries in protecting retinal ganglion cell axons from degenerationfollowing optic nerve transection

TABLE V RT97-RGC axon density 11 days after ON transection CompoundStructure Comments (36 ON axon rescued) B

Adamanti Thioester of urea Ki rotomase = 149 nM Clearance = ? μl/min100.0% ±5.2% SEM A GPI 1046

Ester Ki rotomase = 7.5 nM Clearance = 63.8 μl/min 60.5% ±3.9 SEM C

Sulfonamide Ki rotomase = 107 nM Clearance = 31.1 μl/min 60.4% ±3.1% SEMD

Pipecolic sulfonamide Ki rotomase = nM Clearance = μl/min 58.4% ±6.4%SEM E

Ester of pipecolic acid Ki rotomase = 20 nM Clearance = 41.8 μl/ml 56.6%±9.4% SEM F

Proline heterocycle Analog of GPI 1046 Ki rotomase = 272 nM Clearance =? μl/min 55.1% ±5.9% SEM G

Pipecolic acid dimethyl ketone Ki rotomase >10,000 nM Clearance = ?μl/min 34.0% ±4.8% SEM H

Ki rotomase = nM Clearance = ? μl/min 30.3% ±8.0% SEM I

Ester of Thiourea Ki rotomase = 131 nM Clearance = 8.0 μl/min 23.8% ±5.3SEM J

Ketone analog of GPI 1046 Ki rotomase = 210 nM Clearance = 1.5 μl/min15.8% ±4.8% SEM K

Pipecolic acid Thioester Ki rotomase = 86 nM Clearance = 4.5 μl/min13.0% ±4.2% SEM L

Prolyl acid Ki rotomase = >7743 nM Clearance = 5.2 μl/min 7.8% ±3.0% SEMM

Thioester Ki rotomase = 7 nM Clearance = 12.5 μl/min −6.3% +3.9% SEM N

Ki rotomase = 722 nM Clearance = 21.9 μl/min

Example 16 The FKBP Neuroimmunophilin Ligand GPI-1046 Enhances RetinalGanglion Cell Survival and Arrests Axonal Dying Back Following OpticNerve Transection

Transection of the mammalian optic nerve results in a brief period ofabortive regeneration, but the majority of axotomized neurons die andthe axons from many persisting ganglion cells die back beyond the opticnerve head. The present Example was designed to examine theneuroprotective effects of GPI-1046 following optic nerve transection.

Retinal ganglion cells in adult male Sprague Dawley rats wereretrogradely labeled by fluorogold injection in the LGNd and four dayslater the optic nerves were transected 5 mm behind the globe. Groups ofanimals received either GPI-1046 10 mg/kg/day s.c. or vehicle for 28days. All experimental animals and controls were sacrificed 90 daysafter transection.

By 90 days only—10% of the FG labeled ganglion cell population survivedbut less than half of these neurons maintained axons that extended pastthe optic nerve head, as detected with RT97 neurofilamentimmunohistochemisty. GPI-1046 treatment produced a moderate degree ofperikaryal neuroprotection, sparing 25% of the ganglion cell population,and preserved the axons of virtually all protected neurons in theproximal stump of the transected nerve. These results indicate thattreatment with the FKBP neuroimmunophilin ligand GPI-1046 produces afundamental alteration in the pathological process following injury toCNS tracts.

These results also demonstrate that the small molecule FKBPneuroimmunophilin ligand GPI 1046 enhances neurite outgrowth in culture,enhance peripheral nerve regeneration, and stimulate sprouting withinthe CNS following partial deafferentation.

Example 17 Neuroimmunophilin Ligands Promote Recovery from thePeripheral Sensory Neuropathy Associated with Streptozotocin-inducedDiabetes

Peripheral neuropathy is a common debilitating complication of Type 2diabetes in some 30-40% of diabetic patients. Neurotrophic factors suchas nerve growth factor (NGF) are known to promote survival of developingand adult neurons of the peripheral nervous system (PNS), and have alsobeen evaluated as treatments for diabetic peripheral neuropathy. Some ofthe selective ligands of the neuroimmunophilin FKBP-12 such as the smallmolecule GPI-1046, have also been shown to promote repair andregeneration in the central and peripheral nervous systems (Proc. Nat'l.Acad. Sci. USA 94, 2019-2024, 1997).

In this Example the potential therapeutic effects of GPI-1046 wereevaluated for its ability to improve sensory function in thestreptozotocin-induced diabetic rat. The procedure involved using MaleWistar rats which were given a single injection of streptozotocin (65mg/kg i.v.). Blood glucose levels were determined weekly for the firstthree weeks and on the last week of the experiment. Animals wereevaluated weekly for signs of sensory neuropathy using the conventionalhot plate and tail flick apparatus test procedures. After six weeks,treatment either with GPI-1046 or vehicle was initiated.

The results demonstrated that behavioral testing using the hot plate andthe tail flick apparatus indicated improvement in latency in lesionedanimals treated for 6 weeks with GPI-1046 at 10 mg/kg s.c. The resultsalso showed that GPI-1046 ameliorates the behavioral sequelae ofdiabetic sensory neuropathy and may offer some relief for patientssuffering from diabetic peripheral neuropathy.

Morris Watermaze/Aging and Memory Test Procedure

Aged rodents exhibit marked individual differences in performance on avariety of behavioral tasks, including two-choice spatial discriminationin a modified T-maze, spatial discrimination in a circular platformtask, passive avoidance, radial maze tasks, and spatial navigation in awater pool.

In all of these tasks, a proportion of aged rats or mice perform as wellas the vast majority of young control animals, while other animalsdisplay severe impairments in memory function compared to young animals.For example, Fischer and colleagues showed that the proportion of ratsdisplaying significant impairments in spatial navigation increases withage, (Fischer et al. 1991b) with 8% of all 12 month old, 45% of 18 monthold, 53% of 24 month old, and 90% of all 30 month old rats displayingimpairments in spatial acquisition of the Morris watermaze task relativeto young controls.

Specifically, rodent spatial learning and memory decline during aginghas been accepted by many investigators as an intriguing correlativeanimal model of human senile dementia. Cholinergic function in thehippocampus has been extensively studied as a component of spatiallearning in rodents, and declining hippocampal cholinergic function hasbeen noted in parallel with the development of learning and memoryimpairments. In addition, other neurotransmitter systems have been shownto contribute to spatial learning, and to decline with age, such as thedopaminergic and noradrenergic, serotonergic, and glutamatergic systems.

Also, reports on age-related deficits of hippocampal long-termpotentiation (LTP)-induction, a reduction in theta rhythm frequency, aloss of experience-dependent plasticity of hippocampal place-units, andreductions in hippocampal protein kinase C are in keeping with theconcept that no single underlying pathology can be identified as thecause of age-related behavioral impairment in rodents. However, thevarious experimental therapeutic approaches that have been undertaken toimprove memory function in aged rodents have been somewhat slantedtowards the cholinergic hypothesis.

The Morris watermaze is widely used for assessing spatial memoryformation and retention in experimental animals. The test depends on theanimal's ability to utilize spatial visual information in order tolocate a submerged escape platform in a water tank. It is important thatthe tank itself be as devoid of specific visual features aspossible—thus, it is always circular in shape, the sides are kept smoothand in uniform dull colors, and the water is rendered opaque withnontoxic watercolor pigment or powdered milk. This is to ensure that theanimal navigates only by the use of more distant visual cues, or by theuse of intra-maze cues specifically provided by the experimenter.

The tank is filled to a level which forces the animal to swim actively.Normal mice and rats react aversively to the swimming part of the testand will climb onto, and remain on, an escape platform from which theyare removed to a heated resting cage.

If the platform is visible (i.e. above the surface), animals placed inthe tank will quickly learn to home in on the platform and climb outonto it. Testing with a visible platform will also ensure that theexperimental animals are not blind and show sufficient motivation andstamina to perform the task, which can be important in experimentsinvolving aged rodents. If the platform is invisible (i.e. submergedjust below the surface), normal animals learn to use distant visual cuesin the test room for orientation in the test tank, and, when placed inthe tank, will quickly home in on the approximate location of theplatform and circle in that area until the platform is found.

The animals' path, speed, and swim time are tracked with a ceilingcamera for later computerized analysis. Over the course of severalsuccessive trials, spatial learning can therefore be defined as a dropof distance swum, or time elapsed, from placement in the tank untilescape onto the invisible platform.

The test can be adapted to assess several aspects of spatial memory: a)acquisition of a cued task, where the animal's ability to link onevisual cue directly with the escape platform depends on corticalfunction (i.e. a ball is suspended over the escape platform and theanimal learns to follow this cue to find the platform); b) acquisitionof a spatial task, where the animal's ability to learn the location of asubmerged escape platform based on a combination of distant visual cuesis dependent upon hippocampal function (i.e. the animal learns totriangulate its position in the tank by visually aligning thepaper-tower dispenser with the door and ceiling lamp); c) retention of asuccessfully acquired spatial task, which is predominantly dependant oncortical function (i.e. the animal must remember the spatial location ofthe platform over several weeks); d) a hippocampus-dependant reversaltask where the animals must reacquire a new spatial platform location(i.e. the platform is moved to a new location between swim trials andthe animal must abandon its previous search strategy and acquire a newone).

These different modifications of the Morris watermaze procedure can beapplied in sequence to the same set of experimental animals and allowfor a thorough characterization of their spatial memory performance andits decline with normal ageing. Moreover, such a series of sequentialmemory tests sheds some light on the functional integrity of thespecific brain systems involved in the acquisition and retention ofspatial memory (e.g. rats with cholinergic lesions of the hippocampusmay remember a platform location acquired weeks before, but persevereover the old platform location after the platform is moved).

Example 18 Effects of Chronic GPI-1046 Administration on SpatialLearning and Memory in Aged Rodents

This Example shows the effects of chronic treatment with thesystemically available FKBP-ligand GPI-1046 on spatial learning andmemory in aged rodents.

The procedure involved using three-month old (young) and 18-19 month oldmale C57BL/6N-Nia (aged) mice which habituated to the well known andconventional Morris watermaze during a 4 trials/day, 3-4 day visibleplatform training phase. Subsequent spatial acquisition testing wasconducting as follows: All mice were given 4 trials/day (block), for 5days. Maximum swim time was 90 seconds. Aged mice were allocated to an“aged impaired” group if their performance during blocks 4 or 5 of theacquisition phase was >1 S.D. above the mean of “young” mice, and to an“aged non-impaired” group if their performance was <0.5 S.D. above themean of “young” mice. Aged groups were then split into statisticallysimilar “GPI-1046” and “vehicle” groups.

Daily treatment with 10 mg/kg GPI-1046 was initiated 3 days after theend of acquisition training, and continued through retention testing.Retention testing began after 3 weeks of dosing using the same methodsas the acquisition phase. Swim Distances (cm) were analyzed in a 7×5ANOVA including Groups and Blocks (1-5) as factors in the analysis,treating Blocks as a repeated measure.

The results showed that planned contrasts revealed that there weresignificant differences between the “young”, and “aged impaired-vehicleand GPI-1046” treated groups at the end of the acquisition phase,F_(1.58)=26.75, P=0.0001, and F_(1.58)=17.70, P=0.0001 respectively.While there were no significant differences between the two “agedimpaired” groups, F_(1.58)=0.67, P=0.42. During retention testing,however, “aged impaired-vehicle” treated animals performed significantlypoorer than “aged impaired—GPI-1046”, and “young” animals,F_(1.69)=8.11, P=0.006, and F_(1.69)=25.45, P=0.0001 respectively. Therewas no longer any statistically significant difference between the“young” and “aged impaired”—GPI-1046” treated groups during theretention phase, F_(1.69)=3.09, P=0.08. In summary, systemic treatmentwith GPI-1046 significantly enhanced spatial memory performance of micewith age-related spatial memory impairments.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention and all suchmodifications are intended to be included within the scope of thefollowing claims.

We claim:
 1. A method for treating a vision disorder improving vision,treating memory impairment, or enhancing memory performance in ananimal, which comprises administering to said animal an effective amountof an N-linked urea or carbamate of a heterocyclic thioester compound.2. The method of claim 1, wherein the compound is immunosuppressive. 3.The method of claim 1, wherein the compound has an affinity for anFKBP-type immunophilin.
 4. The method of claim 3, wherein the FKBP-typeimmunophilin is FKBP-12.
 5. The method of claim 1, wherein the visiondisorder is selected from the group consisting of: visual impairment;orbital disorders; disorders of the lacrimal apparatus; disorders of theeyelids; disorders of the conjunctiva; disorders of the cornea;cataract; disorders of the uveal tract; disorders of the retina;disorders of the optic nerve or visual pathways; free radical inducedeye disorders and diseases; immunologically-mediated eye disorders anddiseases; eye injuries; and symptoms and complications of eye disease,eye disorder, or eye injury.
 6. The method of claim 1, which is forimproving naturally-occurring vision in an animal, in the absence of anyopthalmologic disorder, disease, or injury.
 7. The method of claim 1,wherein the compound is of formula (I):

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein: A and B are taken together with the nitrogen and carbon atomsto which they are respectively attached to form a 5-7 membered saturatedor unsaturated heterocyclic ring containing any combination of CH₂ O, S,SO, SO₂, N, NH, and NR₃; X is either O or S; Y is a direct bond to Z,C₁-C₆ straight or branched chain alkyl, or C₂-C₆ straight or branchedchain alkenyl, wherein any of the carbon atoms of said alkyl or alkenylare optionally substituted in one or more position(s) with amino, halo,haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano,nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl,or oxygen to form a carbonyl, or wherein any of the carbon atoms of saidalkyl or alkenyl are optionally replaced with O, NH, NR₃, S, SO, or SO₂;R₃ is selected from the group consisting of hydrogen, C₁-C₆ straight orbranched chain alkyl, C₃-C₆ straight or branched chain alkenyl oralkynyl, and C₁-C₄ bridging alkyl wherein said bridging alkyl forms aheterocyclic ring starting with the nitrogen of NR₁ and ending with oneof the carbon atoms of said straight or branched chain alkyl or alkenyl,and wherein said heterocyclic ring is optionally fused to an Ar group;Ar is an alicyclic or aromatic, mono-, bi- or tricyclic, carbo- orheterocyclic ring, wherein the ring is either unsubstituted orsubstituted with one or more substituent(s) independently selected fromthe group consisting of alkylamino, amido, amino, aminoalkyl, azo,benzyloxy, C₁-C₉ straight or branched chain alkyl, C₁-C₉ alkoxy, C₂-C₉alkenyloxy, C₂-C₉ straight or branched chain alkenyl, C₃-C₈ cycloalkyl,C₅-C₇ cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilido,halo, haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro,nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thioalkyl,thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl, andcarboxylic and heterocyclic moieties, including alicyclic and aromaticstructures; wherein the individual ring size is 5-8 members; whereinsaid heterocyclic ring contains heteroatom(s) independently selectedfrom the group consisting of O, N, and S; and wherein said aromatic ortertiary alkyl amine is optionally oxidized to a corresponding N-oxide;Z is a direct bond, C₁-C₆ straight or branched chain alkyl, or C₂-C₆straight or branched chain alkenyl, wherein any of the carbon atoms ofsaid alkyl or alkenyl are optionally substituted in one or moreposition(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester,alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl,sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, orwherein any of the carbon atoms of said alkyl or alkenyl are optionallyreplaced with O, NH, NR₃, S, SO, or SO₂; C and D are independentlyhydrogen, Ar, C₁-C₆ straight or branched chain alkyl, or C₂-C₆ straightor branched chain alkenyl; wherein any of the carbon atoms of said alkylor alkenyl are optionally substituted in one or more position(s) withC₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, or Ar;wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionallysubstituted with C₁-C₆ alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo,haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano,nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, orsulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionallysubstituted in one or more position(s) with oxygen to form a carbonyl;or wherein any of the carbon atoms of said alkyl or alkenyl areoptionally replaced with O, NH, NR₃, S, SO, or SO₂; W is O, S, CH₂, orH₂; and U is either O or N, provided that: when U is O, then R₁ is alone pair of electrons and R₂ is selected from the group consisting ofAr, C₃-C₈ cycloalkyl, C₁-C₆ straight or branched chain alkyl or alkenyl,and C₂-C₆ straight or branched chain alkyl or alkenyl substituted in oneor more position(s) with Ar, amino, halo, haloalkyl, hydroxy,trifluoromethyl, C₁-C₆ straight or branched chain alkyl, C₂-C₆ straightor branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester,alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl,sulfhydryl, thioalkyl, sulfonyl, and substituted alkyl or alkenylwherein any of the carbon atoms of the alkyl or alkenyl are optionallyreplaced with S, SO, SO₂, O, or NR₃; and when U is N, then R₁ and R₂ areindependently selected from the group consisting of hydrogen, Ar, C₃-C₈cycloalkyl, C₁-C₆ straight or branched chain alkyl or alkenyl, and C₂-C₆straight or branched chain alkyl or alkenyl substituted in one or moreposition(s) with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl,C₁-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chainalkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy,cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl,sulfonyl, and substituted alkyl or alkenyl wherein any of the carbonatoms of the alkyl or alkenyl are optionally replaced with S, SO, SO₂,O, or NR₃; or R₁ and R₂ may be taken together to form a heterocyclicring.
 8. The method of claim 7, wherein Ar is selected from the groupconsisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl,quinolinyl, isoquinolinyl, fluorenyl, and phenyl.
 9. The method of claim1, wherein the compound is of formula (II):

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein: E, F, G and J are independently CH₂, O, S, SO, SO₂, NH or NR₃;X is either O or S; Y is a direct bond to Z, C₁-C₆ straight or branchedchain alkyl, or C₂-C₆ straight or branched chain alkenyl, wherein any ofthe carbon atoms of said alkyl or alkenyl are optionally substituted inone or more positions with amino, halo, haloalkyl, thiocarbonyl, ester,thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino,aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form acarbonyl, or wherein any of the carbon atoms of said alkyl or alkenylare optionally replaced with O, NH, NR₃, S, SO, or SO₂; R₃ is selectedfrom the group consisting of hydrogen, C₁-C₆ straight or branched chainalkyl, C₃-C₆ straight or branched chain alkenyl or alkynyl, and C₁-C₄bridging alkyl wherein said bridging alkyl forms a heterocyclic ringstarting with the nitrogen of NR₁ and ending with one of the carbonatoms of said straight or branched chain alkyl or alkenyl, and whereinsaid heterocyclic ring is optionally fused to an Ar group; Ar is analicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclicring, wherein the ring is either unsubstituted or substituted with oneor more substituent(s) independently selected from the group consistingof alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, C₁-C₉ straightor branched chain alkyl, C₁-C₉ alkoxy, C₂-C₉ alkenyloxy, C₂-C₉ straightor branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl,carbonyl, carboxy, cyano, diazo, ester, formanilido, halo, haloalkyl,hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy,sulfhydryl, sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano,thioester, thioformamido, trifluoromethyl, and carboxylic andheterocyclic moieties, including alicyclic and aromatic structures;wherein the individual ring size is 5-8 members; wherein saidheterocyclic ring contains heteroatom(s) independently selected from thegroup consisting of O, N, and S; and wherein said aromatic or tertiaryalkyl amine is optionally oxidized to a corresponding N-oxide; Z is adirect bond, C₁-C₆ straight or branched chain alkyl, or C₂-C₆ straightor branched chain alkenyl, wherein any of the carbon atoms of said alkylor alkenyl are optionally substituted in one or more position(s) withamino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy,alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any of thecarbon atoms of said alkyl or alkenyl are optionally replaced with O,NH, NR₃, S, SO, or SO₂; C and D are independently hydrogen, Ar, C₁-C₆straight or branched chain alkyl, or C₂-C₆ straight or branched chainalkenyl; wherein any of the carbon atoms of said alkyl or alkenyl areoptionally substituted in one or more position(s) with C₃-C₈ cycloalkyl,C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, or Ar; wherein said alkyl,alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C₁-C₆alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl,ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino,aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein any carbon atomof said alkyl or alkenyl is optionally substituted in one or moreposition(s) with oxygen to form a carbonyl; or wherein any of the carbonatoms of said alkyl or alkenyl are optionally replaced with O, NH, NR₃,S, SO, or SO₂; W is O, S, CH₂, or H₂; and U is either O or N, providedthat: when U is O, then R₁ is a lone pair of electrons and R₂ isselected from the group consisting of Ar, C₃-C₈ cycloalkyl, C₁-C₆straight or branched chain alkyl or alkenyl, and C₂-C₆ straight orbranched chain alkyl or alkenyl substituted in one or more position(s)with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C₁C₆ straightor branched chain alkyl, C₂-C₆ straight or branched chain alkenyl,carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano,nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl,and substituted alkyl or alkenyl wherein any of the carbon atoms of thealkyl or alkenyl are optionally replaced with S, SO, SO₂, O, or NR₃; andwhen U is N, then R₁ and R₂ are independently selected from the groupconsisting of hydrogen, Ar, C₃-C₈ cycloalkyl, C₁-C₆ straight or branchedchain alkyl or alkenyl, and C₂-C₆ straight or branched chain alkyl oralkenyl substituted in one or more position(s) with Ar, amino, halo,haloalkyl, hydroxy, trifluoromethyl, C₁-C₆ straight or branched chainalkyl, C₂-C₆ straight or branched chain alkenyl, carbonyl, thiocarbonyl,ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino,aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, and substituted alkyl oralkenyl wherein any of the carbon atoms of the alkyl or alkenyl areoptionally replaced with S, SO, SO₂, O, or NR₃; or R₁ and R₂ may betaken together to form a heterocyclic ring.
 10. The method of claim 9,wherein Ar is selected from the group consisting of naphthyl, indolyl,furyl, thiazolyl, thienyl, pyridyl, and phenyl.
 11. The method of claim1, wherein the compound is of formula (III):

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein: E, F, and G are independently CH₂, O, S, SO, SO₂, NH and NR₃; Xis either O or S; Y is a direct bond to Z, C₁-C₆ straight or branchedchain alkyl, or C₂-C₆ straight or branched chain alkenyl, wherein any ofthe carbon atoms of said alkyl or alkenyl are optionally substituted inone or more position(s) with amino, halo, haloalkyl, thiocarbonyl,ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino,aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form acarbonyl, or wherein any of the carbon atoms of said alkyl or alkenylare optionally replaced with O, NH, NR₃, S, SO, or SO₂; R₃ is selectedfrom the group consisting of hydrogen, C₁-C₆ straight or branched chainalkyl, C₃-C₆ straight or branched chain alkenyl or alkynyl, and C₁-C₄bridging alkyl wherein said bridging alkyl forms a heterocyclic ringstarting with the nitrogen of NR₁ and ending with one of the carbonatoms of said straight or branched chain alkyl or alkenyl, and whereinsaid heterocyclic ring is optionally fused to an Ar group; Ar is analicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclicring, wherein the ring is either unsubstituted or substituted with oneor more substituent(s) independently selected from the group consistingof alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, C_(l)-C₉straight or branched chain alkyl, C₁-C₉ alkoxy, C₂-C₉ alkenyloxy, C₂-C₉straight or branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇cycloalkenyl, carbonyl, carboxy, cyano, diazo, ester, formanilido, halo,haloalkyl, hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro,nitroso, phenoxy, sulfhydryl, sulfonylsulfoxy, thio, thioalkyl,thiocarbonyl, thiocyano, thioester, thioformamido, trifluoromethyl, andcarboxylic and heterocyclic moieties, including alicyclic and aromaticstructures; wherein the individual ring size is 5-8 members; whereinsaid heterocyclic ring contains heteroatom(s) independently selectedfrom the group consisting of O, N, and S; and wherein said aromatic ortertiary alkyl amine is optionally oxidized to a corresponding N-oxide;Z is a direct bond, C₁-C₆ straight or branched chain alkyl, or C₂-C₆straight or branched chain alkenyl, wherein any of the carbon atoms ofsaid alkyl or alkenyl are optionally substituted in one or moreposition(s) with amino, halo, haloalkyl, thiocarbonyl, ester, thioester,alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl,sulfhydryl, thioalkyl, sulfonyl, or oxygen to form a carbonyl, orwherein any of the carbon atoms of said alkyl or alkenyl are optionallyreplaced with O, NH, NR₃, S, SO, or SO₂; C and D are independentlyhydrogen, Ar, C₁-C₆ straight or branched chain alkyl, or C₂-C₆ straightor branched chain alkenyl; wherein any of the carbon atoms of said alkylor alkenyl are optionally substituted in one or more position(s) withC₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, or Ar;wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionallysubstituted with C₁-C₆ alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo,haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano,nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, orsulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionallysubstituted in one or more position(s) with oxygen to form a carbonyl;or wherein any of the carbon atoms of said alkyl or alkenyl areoptionally replaced with O, NH, NR₃, S, SO, or SO₂; W is O, S, CH₂, orH₂; and U is either O or N, provided that: when U is O, then R₁ is alone pair of electrons and R₂ is selected from the group consisting ofAr, C₃-C₈ cycloalkyl, C₁-C₆ straight or branched chain alkyl or alkenyl,and C₂-C₆ straight or branched chain alkyl or alkenyl substituted in oneor more positions with Ar, amino, halo, haloalkyl, hydroxy,trifluoromethyl, C₁-C₆ straight or branched chain alkyl, C₂-C₆ straightor branched chain alkenyl, carbonyl, thiocarbonyl, ester, thioester,alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl,sulfhydryl, thioalkyl, sulfonyl, and substituted alkyl or alkenylwherein any of the carbon atoms of the alkyl or alkenyl are optionallyreplaced with S, SO, SO₂, O, or NR₃; and when U is N, then R₁ and R₂ areindependently selected from the group consisting of hydrogen, Ar, C₃-C₈cycloalkyl, C₁-C₆ straight or branched chain alkyl or alkenyl, and C₂-C₆straight or branched chain alkyl or alkenyl substituted in one or moreposition(s) with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl,C₁-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chainalkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy,cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl,sulfonyl, and substituted alkyl or alkenyl wherein any of the carbonatoms of the alkyl or alkenyl are optionally replaced with S, SO, SO₂, Oor NR₃; or R₁ and R₂ may be taken together to form a heterocyclic ring.12. The method of claim 11, wherein Ar is selected from the groupconsisting of naphthyl, indolyl, furyl, thiazolyl, thienyl, pyridyl, andphenyl.
 13. The method of claim 1, wherein the compound is of formula(IV):

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein: n is 1, 2 or 3 forming a 5-7 membered heterocyclic ring; X iseither O or S; Y is a direct bond to Z, C₁-C₆ straight or branched chainalkyl, or C₂-C₆ straight or branched chain alkenyl, wherein any of thecarbon atoms of said alkyl or alkenyl are optionally substituted in oneor more position(s) with amino, halo, haloalkyl, thiocarbonyl, ester,thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino,aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form acarbonyl, or wherein any of the carbon atoms of said alkyl or alkenylare optionally replaced with O, NH, NR₃, S, SO, or S)₂; R₃ is selectedfrom the group consisting of hydrogen, C₁-C₆ straight or branched chainalkyl, C₃-C₆ straight or branched chain alkenyl or alkynyl, and C₁-C₄bridging alkyl wherein said bridging alkyl forms a heterocyclic ringstarting with the nitrogen of NR₁ and ending with one of the carbonatoms of said straight or branched chain alkyl or alkenyl, and whereinsaid heterocyclic ring is optionally fused to an Ar group; Ar is analicyclic or aromatic, mono-, bi- or tricyclic, carbo- or heterocyclicring, wherein the ring is either unsubstituted or substituted with oneor more substituent(s) independently selected from the group consistingof alkylamino, amido, amino, aminoalkyl, azo, benzyloxy, C₁-C₉ straightor branched chain alkyl, C₁-C₉ alkoxy, C₂-C₉ alkenyloxy, C₂-C₉ straightor branched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl,carbonyl, carboxy, cyano, diazo, ester, formanilido, halo, haloalkyl,hydroxy, imino, isocyano, isonitrilo, nitrilo, nitro, nitroso, phenoxy,sulfhydryl, sulfonylsulfoxy, thio, thioalkyl, thiocarbonyl, thiocyano,thioester, thioformamido, trifluoromethyl, and carboxylic andheterocyclic moieties, including alicyclic and aromatic structures;wherein the individual ring size is 5-8 members; wherein saidheterocyclic ring contains heteroatom(s) independently selected from thegroup consisting of O, N, and S; and wherein said aromatic or tertiaryalkyl amine is optionally oxidized to a corresponding N-oxide; Z is adirect bond, C₁-C₆ straight or branched chain alkyl, or C₂-C₆ straightor branched chain alkenyl, wherein any of the carbon atoms of said alkylor alkenyl are optionally substituted in one or more position(s) withamino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy,alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl,thioalkyl, sulfonyl, or oxygen to form a carbonyl, or wherein any of thecarbon atoms of said alkyl or alkenyl are optionally replaced with O,NH, NR₃, S, SO, or SO₂; C and D are independently hydrogen, Ar, C₁-C₆straight or branched chain alkyl, or C₂-C₆ straight or branched chainalkenyl; wherein any of the carbon atoms of said alkyl or alkenyl areoptionally substituted in one or more position(s) with C₃-C₈ cycloalkyl,C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, or Ar; wherein said alkyl,alkenyl, cycloalkyl or cycloalkenyl is optionally substituted with C₁-C₆alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl,ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino,aminoalkyl, sulfhydryl, thioalkyl, or sulfonyl; wherein any carbon atomof said alkyl or alkenyl is optionally substituted in one or moreposition(s) with oxygen to form a carbonyl; or wherein any of the carbonatoms of said alkyl or alkenyl are optionally replaced with O, NH, NR₃,S, SO, or SO₂; W is O, S, CH₂, or H₂; and U is either O or N, providedthat: when U is O, then R₁ is a lone pair of electrons and R₂ isselected from the group consisting of Ar, C₃-C₈ cycloalkyl, C₁-C₆straight or branched chain alkyl or alkenyl, and C₂-C₆ straight orbranched chain alkyl or alkenyl substituted in one or more position(s)with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C₁-C₆straight or branched chain alkyl, C₂-C₆ straight or branched chainalkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy,cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl,sulfonyl, and substituted alkyl or alkenyl wherein any of the carbonatoms of the alkyl or alkenyl are optionally replaced with S, SO, SO₂, Oor NR₃; and when U is N, then R₁ and R₂ are independently selected fromthe group consisting of hydrogen, Ar, C₃-C₈ cycloalkyl, C₁-C₆ straightor branched chain alkyl or alkenyl, and C₂-C₆ straight or branched chainalkyl or alkenyl substituted in one or more position(s) with Ar, amino,halo, haloalkyl, hydroxy, trifluoromethyl, C₁-C₆ straight or branchedchain alkyl, C₂-C₆ straight or branched chain alkenyl, carbonyl,thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino,alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, and substitutedalkyl or alkenyl wherein any of the carbon atoms of the alkyl or alkenylare optionally replaced with S, SO, SO₂, O, or NR₃; or R₁ and R₂ may betaken together to form a heterocyclic ring.
 14. The method of claim 13,wherein Ar is selected from the group consisting of naphthyl, indolyl,furyl, thiazolyl, thienyl, pyridyl, and phenyl.
 15. The method of claim13, wherein: n is 1 or 2; Y is (CH₂)₂ or a direct bond; Z is CH; C is3-pyridyl, 4-methoxyphenyl, phenyl, or 2-phenylethyl; D is hydrogen,phenyl or 2-phenylethyl; R₁ is hydrogen; and R₂ is 2-methylbutyl,1,1-dimethylpropyl, cyclohexyl, 1-adamantyl, or phenyl.
 16. The methodof claim 13, wherein the compound is selected from the group consistingof:3-(3-Pyridyl)-1-propyl-2S-1-[(2-methylbutyl)carbamoyl]pyrrolidine-2-carboxylate;3-(3-Pyridyl)-1-propyl-2S-1-[(1′,1′-Dimethylpropyl)carbamoyl]pyrrolidine-2-carboxylate;3-(3-Pyridyl)-1-propyl-2S-1-[(cyclohexyl)thiocarbamoyl]pyrrolidine-2-carboxylate;and pharmaceutically acceptable salts, esters, and solvates thereof. 17.A method for treating a vision disorder, improving vision, treatingmemory impairment, or enhancing memory performance in an animal, whichcomprises administering to said animal an effective amount of a compoundof formula (V):

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein: V is C, N, or S; Y is a direct bond, C₁-C₆ straight or branchedchain alkyl, or C₂-C₆ straight or branched chain alkenyl, wherein anycarbon atom of said alkyl or alkenyl is optionally substituted in one ormore position(s) with amino, halo, haloalkyl, thiocarbonyl, ester,thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino,aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or oxygen to form acarbonyl, or wherein any carbon atom of said alkyl or alkenyl isoptionally replaced with O, NH, NR₃, S, SO, or SO₂; R₃ is selected fromthe group consisting of hydrogen, C₁-C₆ straight or branched chainalkyl, C₃-C₆ straight or branched chain alkenyl or alkynyl, and C₁-C₄bridging alkyl wherein a bridge is formed between the nitrogen and acarbon atom of said straight or branched chain alkyl or alkenylcontaining said heteroatom to form a ring, wherein said ring isoptionally fused to an Ar group; Ar is an alicyclic or aromatic, mono-,bi- or tricyclic, carbo- or heterocyclic ring, wherein the ring iseither unsubstituted or substituted with one or more substituent(s);wherein the individual ring size is 5-8 members; wherein saidheterocyclic ring contains heteroatom(s) independently selected from thegroup consisting of O, N, and S; and wherein said aromatic or tertiaryalkyl amine is optionally oxidized to a corresponding N-oxide; Z is adirect bond, C₁-C₆ straight or branched chain alkyl, or C₂-C₆ straightor branched chain alkenyl, wherein any carbon atom of said alkyl oralkenyl is optionally substituted in one or more position(s) with amino,halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy,cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl,sulfonyl, or oxygen to form a carbonyl, or wherein any carbon atom ofsaid alkyl or alkenyl is optionally replaced with O, NH, NR₃, S, SO, orSO₂; C and D are independently hydrogen, Ar, C₁-C₆ straight or branchedchain alkyl, or C₂-C₆ straight or branched chain alkenyl; wherein saidalkyl or alkenyl is optionally substituted with one or moresubstituent(s) independently selected from the group consisting of C₃-C₈cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, carbonyl oxygen, and Ar;wherein said alkyl, alkenyl, cycloalkyl or cycloalkenyl is optionallysubstituted with C₁-C₆ alkyl, C₂-C₆ alkenyl, hydroxy, amino, halo,haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano,nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, orsulfonyl; wherein any carbon atom of said alkyl or alkenyl is optionallysubstituted in one or more position(s) with oxygen to form a carbonyl;or wherein any carbon atom of said alkyl or alkenyl is optionallyreplaced with O, NH, NR₃, S, SO, or SO₂; A and B are taken toaether withthe nitrogen and carbon atoms to which they are respectively attached toform a 5-7 membered saturated or unsaturated heterocyclic ringcontaining any combination of CH₂ S, SO, SO₂, N, NH, and NR₃; and R₁,R₂, U, W, and X are as defined in claim 7 above.
 18. The method of claim1, wherein the compound is administered to said animal in combinationwith an effective amount of one or more factor(s) useful in treatingvision disorders, improving vision, treating memory impairment, orenhancing memory performance in an animal.
 19. The method of claim 18,wherein the one or more factor(s) is/are selected from the groupconsisting of immunosuppressants for treating autoimmune, inflammatory,and immunologically-mediated disorders; wound healing agents fortreating wounds resulting from injury or surgery; antiglaucomatousmedications for treating abnormally elevated intraocular pressure;neurotrophic factors and growth factors for treating neurodegenerativedisorders or stimulating neurite outgrowth; compounds effective inlimiting or preventing hemorrhage or neovascularization for treatingmacular degeneration; and antioxidants for treating oxidative damage toeye tissues.
 20. The method of claim 1, wherein the compound isnon-immunosuppressive.